Mitochondrion[JOURNAL]
Sun
200 papers
Exogenous mitochondrial transfer alleviates neurodegeneration in Parkinson's disease model by improving mitochondrial function.
Si Y, Hayat MA, Ni Y … +11 more , Zhang J, Guo T, Cao Y, Hong Y, Zuo H, Sun X, Li Z, Chen B, Wan J, Wang Y, Hu J
Mitochondrion · 2026 Mar · PMID 41605329 · Publisher ↗
Parkinson's disease (PD) is the second most common neurodegenerative disorder related to mitochondrial dysfunction. Recent studies have reported that mitochondrial transfer between cells occurred naturally and was effect...
Parkinson's disease (PD) is the second most common neurodegenerative disorder related to mitochondrial dysfunction. Recent studies have reported that mitochondrial transfer between cells occurred naturally and was effective for alleviating mitochondrial dysfunction. In the current study, functional exogenous mitochondria (Mito) were extracted and administered to both in vitro and in vivo PD models, exploring the therapeutic effects of Mito on damaged neurons. It was observed that in the in vitro PD model, Mito improved cell morphology and increased cell viability from 25.06% to 42.44% (p < 0.001), while enhancing mitochondrial activity within the cells by a 201% increase in the JC-1 red/green fluorescence ratio (p = 0.02). Further analysis suggests that Mito's neuroprotective effects are potentially mediated via integrated modulation of neuroinflammation and ferroptosis pathways. The findings of the in vivo PD model showed that Mito improved motor coordination in the rotational test by 71% (p < 0.01) and ameliorated depression-like behavior demonstrating a 13.4% enhancement in Sucrose preference (p < 0.001), accompanied by histological evidence of neuroprotection observed in Nissl-stained brain sections and the significant recovery in mitochondrial function by 31.6% (p = 0.01). This study is the first to demonstrate that Mito can enter a PD cell model and rescue neuronal and mitochondrial damage in both in vivo and in vitro settings, with transcriptomic analysis revealing the involvement of key molecular pathways related to neuroinflammation and ferroptosis. This offers new insights and prospectus therapeutic strategies for PD as well as a foundation for future research in clinical medicine.
Mitochondrial dysfunction-induced PANoptosis: Mechanisms, triggers, and disease implications.
Pan L, Fang S, Kong F … +2 more , Ye S, Xiong Y
Mitochondrion · 2026 May · PMID 41592633 · Publisher ↗
In recent years, PANoptosis, as a novel form of cell death that integrates multiple cell death pathways, has progressively emerged as a cutting-edge research field in the study of cell death and immune regulation. PANopt...
In recent years, PANoptosis, as a novel form of cell death that integrates multiple cell death pathways, has progressively emerged as a cutting-edge research field in the study of cell death and immune regulation. PANoptosis, a recently proposed form of inflammatory programmed cell death, integrates features of pyroptosis, apoptosis, and necroptosis, while emphasizing their interplay. It is mediated by the PANoptosome and plays a pivotal role in infections, inflammation, tumors, and degenerative diseases. Recent studies have demonstrated that ROS serve as critical signaling molecules for PANoptosome assembly. Given that mitochondria constitute the primary intracellular source of ROS, this establishes a crucial link between mitochondrial and PANoptosis activation. Mitochondria sustain energy production, calcium homeostasis, and signaling but also contribute to immune responses and cell death. Oxidative stress, obesity, and environmental pollutants can induce mitochondrial dysfunction, manifested through impaired mitochondrial dynamics, which subsequently leads to excessive ROS production and mtDNA leakage. These pathological changes ultimately trigger PANoptosis activation. This review systematically summarizes how mitochondrial dysfunction triggers PANoptosis through mechanisms such as ROS accumulation, aberrant mitochondrial dynamics, and mtDNA leakage. Furthermore, it explores the implications of this process in traumatic brain injury, inflammatory diseases, ischemic disorders, and diseases induced by environmental toxins (e.g., microplastics and heavy metals). Understanding the interplay between mitochondria and PANoptosis may provide critical insights into the pathogenesis of inflammation-related diseases and offer novel mitochondria-targeted therapeutic strategies.
Mitochondrial responses to thermal stress: ROS dynamics and metabolic shifts in Drosophila.
Léger A, Herpe L, Pichaud N
Mitochondrion · 2026 Mar · PMID 41592632 · Publisher ↗
Temperature critically impacts ectotherm metabolism, notably mitochondrial respiration, enzyme activity, and ATP production. However, the effect of temperature on reactive oxygen species (ROS) production remains poorly u...
Temperature critically impacts ectotherm metabolism, notably mitochondrial respiration, enzyme activity, and ATP production. However, the effect of temperature on reactive oxygen species (ROS) production remains poorly understood in these organisms. Here, we investigated the thermal sensitivity of HO production by isolated mitochondria from Drosophila melanogaster. We measured HO emission rates at six temperatures (18-45 °C) during: (i) oxidative phosphorylation (OXPHOS) fueled by NADH-linked substrates feeding electrons into complex I (CI), as well as by FADH-linked substrates such as proline, succinate, and glycerol-3-phosphate (G3P); and (ii) during non-phosphorylating conditions with FADH-linked substrates as well as using defined substrate/inhibitor combinations such as pyruvate, malate and rotenone (P/M-driven), as well as supported by proline, succinate, and G3P when inhibitors are present. We calculated relative HO emission rates and compared them with previously measured enzyme activities and oxygen consumption rates. Our results show marked thermal sensitivity of HO emission during OXPHOS and when P/M-driven. At elevated temperatures, increased ROS production by NADH-linked substrates during OXPHOS coincided with a decline in CI-induced oxygen consumption capacity and pyruvate dehydrogenase (PDH) activity, indicating a dysfunction in NADH-producing and -consuming systems. In contrast, substrates feeding electrons into the Q pool via FADH oxidation support respiration at high temperature decoupled from ROS production, suggesting a metabolic strategy to sustain respiration while limiting oxidative stress. These findings highlight that mitochondrial thermal sensitivity involves a complex regulation of ROS metabolism. Our study provides new insights into mitochondrial ROS dynamics and their implications for upper thermal tolerance in insects.
Serum cell-free mitochondrial DNA under a highly standardized and controlled stress induction.
Herhaus B, Daubermann C, Neuberger EWI … +2 more , Simon P, Petrowski K
Mitochondrion · 2026 Mar · PMID 41592631 · Publisher ↗
Cell-free mitochondrial DNA (ccf-mtDNA) is increasingly recognized as a biomarker of stress-related mitochondrial dysfunction. Acute psychological stress may induce ccf-mtDNA release, underscoring its potential role in s...
Cell-free mitochondrial DNA (ccf-mtDNA) is increasingly recognized as a biomarker of stress-related mitochondrial dysfunction. Acute psychological stress may induce ccf-mtDNA release, underscoring its potential role in stress physiology and adaptation. To further investigate this relationship, the present study examined acute stress-induced ccf-mtDNA dynamics in a controlled experimental setting. Twenty-seven healthy males (mean age: 23.78 ± 3.90 years) underwent both the Trier Social Stress Test (psychological stressor) and a resting condition. The kinetics of serum cell-free mitochondrial DNA (ccf-mtDNA) and serum cortisol were measured before and at 8 time points up to 105 min after the two stress conditions. After the TSST, ccf-mtDNA showed significant transient increases at +20 and +75 min, whereas cortisol exhibited the expected robust stress response. Our findings suggest that acute psychological stress can induce transient and heterogeneous changes in serum ccf-mtDNA, though these dynamics appear more modest and delayed than cortisol responses. Variability across studies underscores the need for standardized protocols and further research to clarify the mechanisms and moderators of ccf-mtDNA release under stress.
Transcriptional activation by MNRR1 is effected by recruiting p300 and can be induced by minimal peptides.
Purandare N, Pasupathi V, Padhan D … +3 more , Rai S, Grossman LI, Aras S
Mitochondrion · 2026 May · PMID 41592630 · Publisher ↗
Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22, AAG10), which functions in both the mitochondria and the nucleus, modulates mitochondrial function as well as cellular stress response. We have p...
Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22, AAG10), which functions in both the mitochondria and the nucleus, modulates mitochondrial function as well as cellular stress response. We have previously shown that stress response is predominantly mediated by its nuclear function as a transcriptional regulator at an 8-bp DNA element. This 8-bp element is the consensus DNA binding site for the transcription factor Recombination Signal Binding Protein For Immunoglobulin Kappa J Region (RBPJk). Here we have refined the mechanism by which MNRR1 regulates transcription at the ORE. We show that MNRR1 interacts with RBPJk and recruits the transcriptional co-activator p300 to facilitate transcription. We also show that a minimal domain of MNRR1 is sufficient to activate its nuclear function. Peptides based on this minimal domain can activate transcription by MNRR1 by enhancing p300 and RBPJk interaction. MNRR1 peptides activate downstream pathways such as mitochondrial biogenesis and the unfolded protein response (UPRmt) in an in vitro model for MELAS.
PP2A inhibition alleviates DCD liver damage during prolonged cold ischemia by interfering Drp1 translocation and ER stress.
Lan J, Lu Z, Cheng Q … +3 more , Sun Y, Ye S, Xiong Y
Mitochondrion · 2026 May · PMID 41587672 · Publisher ↗
Prolonged cold ischemia-warm reperfusion (PCI/WR) of donor livers is an independent risk factor for primary nonfunction (PNF) after liver transplantation (LT). Previous studies have demonstrated that may be related to he...
Prolonged cold ischemia-warm reperfusion (PCI/WR) of donor livers is an independent risk factor for primary nonfunction (PNF) after liver transplantation (LT). Previous studies have demonstrated that may be related to hepatocyte apoptosis mediated by the abnormal mitochondrial division. In the present study, we report that PCI/WR up-regulated apoptotic signals in donation after circulatory death (DCD) rat livers after 24 h of cold ischemia, increased the expression of PP2A, Drp1 and CHOP, and led to caspase-induced apoptosis. Downregulation of PP2A attenuated PCI/WR-induced hepatocyte injury, improved liver function, and decreased the expression of Drp1 and CHOP. In particular, okadaic acid (OA) inhibited the translocation of Drp1 to mitochondria and the release of Cyt c into the cytoplasm. Further investigation found that inhibiting mitochondrial division or ER-stress could slightly reverse the apoptosis rate induced by PCI/WR, while not affecting PP2A expression in vivo or in vitro. These observations indicated that PP2A involved in the regulation of hepatocyte apoptosis after prolonged cold storage, possibly through inhibiting the expression of Drp1 and CHOP, as well as Drp1 translocation. Our results provide evidence that PP2A could be a potential target for therapeutic intervention of DCD livers subjected to prolonged cold ischemia.
Mitochondria transfer from myocytes to endothelial cells promotes angiogenesis in skeletal muscle.
Long YF, Huang AJ, Tang S … +10 more , Xu Z, Wu MY, Liu K, Chen ZC, Qin L, Dai BY, Dong C, Cheung WH, Wang XL, Yang DZ
Mitochondrion · 2026 Mar · PMID 41587671 · Publisher ↗
Skeletal muscle and vascular health are closely interconnected, yet the mechanisms underlying their crosstalk remain poorly understood. This study investigates the role of mitochondria transfer from myocytes to endotheli...
Skeletal muscle and vascular health are closely interconnected, yet the mechanisms underlying their crosstalk remain poorly understood. This study investigates the role of mitochondria transfer from myocytes to endothelial cells. Using in vitro 2D and 3D coculture systems, combined with protein-level and functional analyses, we show that mitochondria are transferred via extracellular vesicles in a Rab7-dependent and cellular connection-independent manner. Connexin 43 (CX43) inhibition downregulating Growth-Associated Protein 43 (GAP43) but enhances mitochondria transfer, accompanied by increasing Rab7. Transferred mitochondria promote endothelial cells proliferation, migration, ATP production, and angiogenesis, which could be the key processes in preserving vascular integrity and muscle function. Our study indicated that the aging-associated decline in CX43 and mitochondrial quality exacerbates muscle atrophy by facilitating the transfer of dysfunctional mitochondria. These findings uncover a novel mechanism of muscle-vessel communication and highlight mitochondria transfer as a potential therapeutic target for aging-related muscular and vascular deterioration. New and Noteworthy. Mitochondria transfer is a way for cell communication. However, mitochondria transfer between myocyte and endothelial cell remains unknown. Here, we demonstrates that mitochondria transfer occurs between myocytes and endothelial cells. Interestingly, inhibition of CX43 leads to a decrease in GAP43 expression, while simultaneously upregulating Rab7 and enhancing mitochondria transfer from myocytes to endothelial cells. Furthermore, we reveal that Rab7-induced mechanism mediates the transfer of both functional and impaired mitochondria from myocytes to endothelial cells.
Sensitivity of primary mitochondrial disease fibroblasts to ferroptosis: The role of intracellular iron.
Pecheritsyna S, Ermert ME, Podhumljak E … +5 more , Pennings B, Zondag R, Iannetti EF, Renkema H, Smeitink J
Mitochondrion · 2026 Mar · PMID 41581630 · Publisher ↗
Primary mitochondrial diseases (PMDs) are directly linked to oxidative phosphorylation (OXPHOS) dysfunction. Here, we investigated the selective sensitivity of PMD patient fibroblasts compared to healthy control primary...
Primary mitochondrial diseases (PMDs) are directly linked to oxidative phosphorylation (OXPHOS) dysfunction. Here, we investigated the selective sensitivity of PMD patient fibroblasts compared to healthy control primary human skin fibroblasts (PHSF) to ferroptosis, and the role of iron in this cell death mechanism. To address this, we investigated sensitivity to ferroptosis inducers, the effects of iron supplementation, and intracellular iron pools. The selectivity of PMD fibroblasts ferroptotic cell death was found to be more pronounced with class 1 ferroptosis inducers (FINs) that deplete GSH than upon direct GPX4 inhibitors. Notably, exogenous iron discriminatory triggered ferroptosis in patient fibroblasts and enhanced BSO-induced cell death in both patient and control cells. Further study revealed elevated basal levels of labile iron in patient fibroblasts, but mRNA analysis of iron-regulating genes did not reveal major expression differences. These findings suggest that increased labile iron predisposes PMD fibroblasts to ferroptosis. Complementation of defective OXPHOS restored ferroptosis sensitivity and LIP levels in a cell line with an NDUFS7 mutation, indicating a functional relationship caused by OXPHOS deficiency. Further understanding this interplay may provide insights into therapeutic strategies targeting iron homeostasis to mitigate ferroptotic cell death in PMDs.
Biallelic FOXRED1 mutations cause infantile mitochondrial encephalopathy with complex I disassembly and basal ganglia degeneration.
Pan C, Zhu R, Huang X … +10 more , Duan H, Wu T, Wang X, Ding Y, Chen C, He F, Peng J, Yin F, Lou X, Yang L
Mitochondrion · 2026 Mar · PMID 41412221 · Publisher ↗
Developmental and epileptic encephalopathy (DEE) is a severe neurological disorder. Biallelic mutations in the nuclear-encoded mitochondrial chaperone gene FOXRED1, a specific assembly factor for complex I, cause mitocho...
Developmental and epileptic encephalopathy (DEE) is a severe neurological disorder. Biallelic mutations in the nuclear-encoded mitochondrial chaperone gene FOXRED1, a specific assembly factor for complex I, cause mitochondrial dysfunction; however, their role in DEE pathogenesis remains unexplored. Clinical data and peripheral blood mononuclear cells (PBMCs) were obtained from two patients with compound heterozygous FOXRED1 mutations (c.850T>C (p.C284R)/c.1054C>T (p.R352W) and c.1054C>T (p.R352W)/c.3dup (p.I2Dfs*35) and age-matched controls. Mitochondrial phenotyping, included complex I activity, mitochondrial respiration stress test, membrane potential, intracellular ROS, and NAD/NADH ratio, were performed. Both patients exhibited early-onset refractory seizures, basal ganglia lesions, hyperlacticemia, and developmental regression. FOXRED1 mutations resulted in 50% reduction in complex I activity, dissasembly of complex I, mitochondrial depolarization, oxidative stress, and NAD/NADH imbalance. Niacin restored the NAD/NADH ratio in vitro, while clinical supplementation reduced blood lactate levels, suggesting it may be a potential therapeutic option.
Aagab-driven SHIP2 degradation rescues mitochondrial dysfunction in hypoxic-ischemic encephalopathy.
Han J, He L, Chen L … +2 more , Wen B, Ji J
Mitochondrion · 2026 Mar · PMID 41412220 · Publisher ↗
Neonatal hypoxic-ischemic encephalopathy (HIE), a central nervous system disorder caused by oxygen deprivation and reduced cerebral blood flow, involves complex mechanisms including mitochondrial oxidative stress and neu...
Neonatal hypoxic-ischemic encephalopathy (HIE), a central nervous system disorder caused by oxygen deprivation and reduced cerebral blood flow, involves complex mechanisms including mitochondrial oxidative stress and neuronal injury. The Rab-like GTPase domain-containing protein Aagab has been linked to neuronal regulation by modulating neural precursor cell expressed, developmentally down-regulated protein 4-1 (NEDD4-1)-mediated ubiquitination and degradation of Src homology 2 domain-containing inositol 5-phosphatase 2 (SHIP2). In this study, we investigated the contribution of the Aagab-NEDD4-1-SHIP2 axis to hypoxic-ischemic encephalopathy (HIE) and its influence on mitochondrial oxidative stress. Multi-omics analyses of publicly available RNA sequencing and proteomic datasets from HIE and control rat brain tissues identified SHIP2 as a significantly upregulated gene strongly associated with oxidative stress pathways. In an oxygen-glucose deprivation (OGD) neuronal model, lentiviral knockdown of SHIP2 enhanced neuronal viability, reduced reactive oxygen species production, and restored mitochondrial membrane potential. In vivo, tail-vein delivery of lentiviral vectors to silence SHIP2 in neonatal rat HIE models led to marked improvements in neurological outcomes, including reduced escape latency in the Morris water maze, increased success rates in the ladder-rung test, and diminished brain lesion area. Mechanistic assays demonstrated that Aagab overexpression increased NEDD4-1 levels, promoted SHIP2 ubiquitination, and accelerated its degradation, whereas NEDD4-1 knockdown reversed these effects. Collectively, these findings indicate that Aagab facilitates NEDD4-1-mediated SHIP2 ubiquitination and degradation, thereby alleviating mitochondrial oxidative stress and mitigating HIE-associated neuronal injury. The Aagab-NEDD4-1-SHIP2 regulatory axis may represent a promising molecular target for therapeutic intervention in HIE.
Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.
Calais H, Bertolin G
Mitochondrion · 2026 Mar · PMID 41352471 · Publisher ↗
Mitochondrial protein import is necessary to ensure the proper functioning of the organelle of the cell as a whole. More than 1000 proteins are synthesized on cytosolic ribosomes and then imported into mitochondria throu...
Mitochondrial protein import is necessary to ensure the proper functioning of the organelle of the cell as a whole. More than 1000 proteins are synthesized on cytosolic ribosomes and then imported into mitochondria through translocases such as TOMM and TIMM complexes. Upon entry, they can reach their final mitochondrial compartment, namely the outer mitochondrial membrane (OMM), the intermembrane space (IMS), the inner mitochondrial membrane (IMM), and the matrix. In this review, we will first explore the main mitochondrial protein import mechanisms. Then, we will focus on how import deficiencies may trigger stress paradigms. Stress response pathways are activated to restore correct cellular homeostasis. We will explore four interconnected pathways at the cellular or mitochondrial scale, which can compensate for import alterations. These are the DELE1-HRI axis combined with the ISR, the UPRam, the UPRmt, and mitophagy. Their activation depends on the extent of import alteration, with ISR and UPRmt pathways activated in conditions of low stress. If stress levels are too high, the elimination of dysfunctional mitochondria by mitophagy is triggered. Last, we will explore how mitochondrial import deficiencies are a feature common to multifaceted pathologies, such as neurodegenerative diseases and cancer. We will also present pharmacological compounds mimicking stress response mechanisms and that could be used as a therapeutic option in the near future to restore efficient mitochondrial protein import rates. Overall, this review highlights the critical role of mitochondrial protein import in cellular and mitochondrial stress response, and in disease pathogenesis. It also emphasizes the potential of mitochondrial protein import as a therapeutic target, despite the surprising absence of direct pharmacological treatments to date.
Dysregulation of RUNX1 isoforms drives mitochondrial defects during neural differentiation in down syndrome.
Liu YN, Cai Q, Li KY … +4 more , Li WX, He G, Zeng F, Yan JB
Mitochondrion · 2026 Mar · PMID 41349757 · Publisher ↗
Down syndrome (DS) is distinguished by neurodevelopmental abnormalities, with mitochondrial dysfunction. The Runt-related transcription factor 1 (RUNX1) gene, located within the Down Syndrome Critical Region (DSCR), is k...
Down syndrome (DS) is distinguished by neurodevelopmental abnormalities, with mitochondrial dysfunction. The Runt-related transcription factor 1 (RUNX1) gene, located within the Down Syndrome Critical Region (DSCR), is known to encode three major isoforms (RUNX1a, RUNX1b and RUNX1c) that play essential roles in neurodevelopmental processes. Our previous research demonstrated that RUNX1 overexpression induces mitochondrial dysfunction in DS-induced pluripotent stem cells (DS-iPSCs). However, the functional impacts of altered expression levels of these RUNX1 isoforms on mitochondrial function, as well as the regulatory mechanisms governing their expression in neural stem cells (NSCs), remain to be elucidated. In this study, our results revealed that DS-NSCs exhibited reduced oxidative phosphorylation and an increased number of mitochondria with structural damage. Consistently elevated RUNX1b and RUNX1c transcription levels were consistently observed in DS peripheral blood mononuclear cells, iPSCs and NSCs. Overexpression of RUNX1c in NSCs not only suppressed RUNX1a expression but also resulted in a substantial decrease in mitochondrial ATP production rate and a significant elevation in reactive oxygen species (ROS) levels. In contrast, knockdown of RUNX1c not only reduced ROS levels but also restored the impaired oxidative phosphorylation in DS-NSCs. Furthermore, our findings revealed that the downregulation of LINC01426, a long non-coding RNA located adjacent to RUNX1, during the neural differentiation of DS-iPSCs resulted in the overexpression of RUNX1c, owing to the reduced interaction with the splicing factor. These findings collectively indicate that the LINC01426-mediated activation of RUNX1c isoforms contributes to mitochondrial dysfunction and morphological abnormalities, ultimately leading to impaired neural differentiation in DS.
The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.
Busch JD, Schöndorf T, Milenkovic D … +7 more , Li X, Wibom R, Silva-Rodrigues JF, Filograna R, Koolmeister C, Larsson NG, Rubalcava-Gracia D
Mitochondrion · 2026 Jan · PMID 41253195 · Publisher ↗
The mitochondrial cytochrome c oxidase (COX, complex IV), a multi-subunit protein complex, plays a crucial role in cellular respiration by reducing oxygen to water and simultaneously pumping protons to enable oxidative p...
The mitochondrial cytochrome c oxidase (COX, complex IV), a multi-subunit protein complex, plays a crucial role in cellular respiration by reducing oxygen to water and simultaneously pumping protons to enable oxidative phosphorylation (OXPHOS). Thus, defects in its assembly can directly affect cellular energy homeostasis. COX20 is an essential chaperone for the core subunit COX2. In human cultured cells, TMEM177 was found to stabilize COX20 and maintain balanced COX2 levels. In mice, TMEM177 was also identified as an interactor of mitochondrial ribosomes. To understand the function of TMEM177 in vivo, we generated Tmem177 knockout mice. Here, we analyze how TMEM177 loss affects mitochondrial gene expression, as well as the activity and assembly of OXPHOS complexes. We found that a small proportion of the knockout mice died perinatally, while surviving knockout mice tended to gain less weight. TMEM177 depletion moderately reduced COX20 levels, but OXPHOS complexes were preserved. Moreover, Tmem177 and Surf1 double knockout mice were born asymptomatic. In conclusion, TMEM177 fine-tunes complex IV assembly by stabilizing COX20 in vivo. Our findings refine the current model of complex IV assembly in mammals.
A 3-hit metabolic signaling model for the core symptoms of autism spectrum disorder.
Naviaux RK
Mitochondrion · 2026 Mar · PMID 41242673 · Publisher ↗
A 3-hit metabolic signaling model of the causes of autism spectrum disorder (ASD) is described. The 3-hits required for ASD are: 1) inheritance of a genotype that sensitizes mitochondria and/or eATP-stimulated, intracell...
A 3-hit metabolic signaling model of the causes of autism spectrum disorder (ASD) is described. The 3-hits required for ASD are: 1) inheritance of a genotype that sensitizes mitochondria and/or eATP-stimulated, intracellular calcium signaling to environmental change, 2) early exposure to environmental triggers that activate the metabolic features of the cell danger response (CDR), and 3) recurrent or persistent exposure to CDR-activating triggers for at least 3-6 months during the critical neurodevelopmental window from the late 1st trimester of pregnancy to the first 18-36 months of life. The three hits associated with an increased risk of ASD can be functionally classified as primers, triggers, and amplifiers of the CDR, respectively. Since the CDR is maintained by metabolic signaling, this new model creates a unified intellectual framework for understanding how the diverse features of ASD are connected. The example of phenylketonuria (PKU) is given to show that even disorders with very strong genetic predispositions can follow this 3-hit developmental paradigm and still be treatable using the principles of metabolic signaling. Since the 2nd and 3rd hits are modifiable, this model predicts that if the children at greatest risk can be diagnosed and treated before symptoms occur, some of these children may never develop ASD, and if diagnosed after symptoms occur, the core symptoms that are most disabling can be decreased significantly.
Assessment of mitochondrial viability under calcium Stress: Insights for mitochondrial transplantation.
Toosky M, Kheradvar A
Mitochondrion · 2026 Jan · PMID 41238093 · Full text
Mitochondrial transplantation has emerged as a promising cardioprotective strategy for ischemia-reperfusion injury, aiming to restore bioenergetic function by delivering healthy mitochondria to damaged tissue. However, c...
Mitochondrial transplantation has emerged as a promising cardioprotective strategy for ischemia-reperfusion injury, aiming to restore bioenergetic function by delivering healthy mitochondria to damaged tissue. However, conflicting reports exist regarding whether mitochondria can survive exposure to the calcium-rich extracellular environment, such as the bloodstream, prior to cellular uptake. Resolving this question is essential for advancing the therapeutic use of mitochondria in clinical settings. Isolated mitochondria from L6 rat skeletal muscle cells were incubated with physiologic (1.3 mM), sub-physiologic (0.65 mM), and supraphysiologic (2.6 mM) concentrations of calcium. Mitochondrial membrane potential was assessed using MitoTracker™ Red FM fluorescence, and structural integrity was evaluated using impedance-based Coulter counter analysis over a 12-hour time course. Mitochondria exposed to 1.3 mM calcium retained 90-95 % membrane potential by 12 h, while 2.6 mM calcium caused progressive loss of function and integrity, approaching levels seen in freeze-thawed controls. Coulter counter measurements revealed more extensive mitochondrial loss across all calcium-treated groups than fluorescence assays alone, suggesting that dye-based methods may underestimate structural damage. Nonetheless, a substantial proportion of mitochondria remained both structurally and functionally intact at physiologically relevant calcium levels. These findings demonstrate that a substantial number of mitochondria can retain membrane potential and structural integrity after exposure to extracellular calcium concentrations approximating those found in blood. This supports the feasibility of intracoronary mitochondrial transplantation and underscores the need for further in vivo studies to optimize survival and efficacy of mitochondria delivered in calcium-rich environments.
Intravenous mitochondrial transplantation as an adjunctive therapy for dilated cardiomyopathy.
Varlik T, Algan D, Sönmez Ö … +5 more , Singh KK, Ülger Ö, Kubat GB, Koch J, Yilmaz Z
Mitochondrion · 2026 Jan · PMID 41232739 · Publisher ↗
Dilated cardiomyopathy (DCM) is one of the most prevalent myocardial disorders in various animals. The underlying causes of DCM are complex and often involve multiple contributing mechanisms. Mitochondrial dysfunction ha...
Dilated cardiomyopathy (DCM) is one of the most prevalent myocardial disorders in various animals. The underlying causes of DCM are complex and often involve multiple contributing mechanisms. Mitochondrial dysfunction has been identified as a key factor in the progression of cardiomyocyte apoptosis. We investigated whether the transplantation of healthy mitochondria improves cardiac function by enhancing the contractile function of myocytes. A 6-year-old dog with cardiomyopathy received platelet-derived, viable mitochondria from a healthy donor as adjunctive therapy alongside standard medical management. Mitochondria were isolated from platelets and administered as a single intravenous bolus at a dose of 81,125 μg/mL. This procedure was carried out under continuous ECG and vital signs monitoring. Ventricular systolic function was assessed at multiple intervals using conventional echocardiography and two-dimensional speckle tracking imaging. Our study revealed notable improvement in systolic performance as early as two hours post-transplantation of mitochondria, with enhanced contractility sustained up to 24 h. These studies suggest mitochondrial transplantation may offer a promising intervention or adjunct to conventional treatments for cardiac dysfunction. This report presents the first documented case of intravenous mitochondrial transplantation in canine DCM.
Mitochondrial-ER crosstalk: An emerging mechanism in the pathophysiology of pulmonary arterial hypertension.
Chaturvedi G, Dubey N, Panchbhai P … +6 more , Singh S, Singh R, Baitha U, Parakh N, Narang R, Yadav HN
Mitochondrion · 2026 Jan · PMID 41223909 · Publisher ↗
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by hyperproliferation and remodeling of the pulmonary vasculature, primarily affecting pulmonary arterial smooth muscle cells (PASMCs...
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by hyperproliferation and remodeling of the pulmonary vasculature, primarily affecting pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs). Although several pharmacological agents target the known signaling pathways in these cells, current therapies fail to reverse vascular remodeling, underscoring the urgent need for novel therapeutic strategies. Recent research has shifted focus towards intracellular organelles, specifically mitochondria and the endoplasmic reticulum (ER), as potential therapeutic targets. A key area of interest is mitochondria-associated membranes (MAMs), specialized contact sites between mitochondria and the ER that regulate essential cellular processes, including calcium homeostasis, ER stress signaling, autophagy, and insulin signaling. This review explores the emerging role of MAMs in the pathogenesis of PAH, detailing the molecular players involved in MAM formation and function. Emphasis is placed on identifying MAM-associated proteins that are dysregulated in PASMCs and PAECs, providing insights into their potential as novel therapeutic targets in PAH.
Complex IV deficiency due to COX4I1 deep intronic and de novo variants results in progressive motor impairment and Leigh syndrome.
Ugarteburu O, Farré-Tarrats L, Muñoz-Pujol G … +14 more , Unceta M, Las Heras J, Garcia-Ribes A, Arza-Ruesga A, de la Morena B, Arauz-Garofalo G, Gay M, Garrabou G, Corral J, Vilaseca M, Ribes A, García-Villoria J, Gort L, Tort F
Mitochondrion · 2026 Jan · PMID 41203052 · Publisher ↗
COX4I1 gene encodes cytochrome c oxidase subunit 4 isoform 1, involved in the early assembly stages of mitochondrial respiratory chain complex IV. To date, COX4I1 pathogenic variants have been reported in only a few case...
COX4I1 gene encodes cytochrome c oxidase subunit 4 isoform 1, involved in the early assembly stages of mitochondrial respiratory chain complex IV. To date, COX4I1 pathogenic variants have been reported in only a few cases, each exhibiting heterogeneous clinical phenotypes and limited functional data. Here, we describe the fourth reported case of COX4I1 deficiency associated with human disease, expanding the phenotypic and genetic spectrum of this rare mitochondrial disorder and providing novel clinical, molecular, and functional data. The herein reported individual presented with progressive deterioration of motor skills, intellectual disability and brain imaging abnormalities compatible with Leigh syndrome. Genetic studies combining short and long read next generation sequencing uncovered a peculiar genetic combination in this patient, harboring a de novo COX4I1 nonsense substitution in trans with an inherited deep intronic variant (c.[64C>T];[73+1511A>G]; p.[Arg22Ter];[Glu25ValfsTer9]). Functional studies performed in patient's tissues and transiently transfected cell lines demonstrated that the identified variants mainly exert their pathogenic effect by targeting COX4I1 protein levels, thereby impairing the proper assembly and activity of complex IV.Additionally, proteomic data in patient's fibroblasts suggested an underlying pathomechanism that involves not only the regulation of complex IV function but also the levels of mitoribosomal proteins. In summary, our findings shed light to clarify some of the main clinical features associated with COX4I1 deficiency and the molecular mechanisms involved in the pathogenesis of this disorder.
The evolving landscape of mitochondrial base editing: advances in precision, modeling, and therapeutic potential.
Shelke P, Tribhuvan S, Agrahari AK … +1 more , Saxena R
Mitochondrion · 2026 Jan · PMID 41173131 · Publisher ↗
The recent development of mitochondrial base editors (mitoBEs) has ushered in a transformational time that has overcome some long-standing limitations in the field of mitochondrial genetics. By closely tracing mitoBE dev...
The recent development of mitochondrial base editors (mitoBEs) has ushered in a transformational time that has overcome some long-standing limitations in the field of mitochondrial genetics. By closely tracing mitoBE development from the earliest tool mitochondria targeted TALENs to the most recent base editing systems that can precisely convert C•G → T•A and A•T → G•C, we review mitoBEs. We describe the development of recent advancements in mitoBEs including the generation of second generation mitoBEs (mitoBEs v2), which have evidence to identify over 70 mouse mtDNA mutations comparable to human pathogenic variants. Notably, in order to incorporate circular RNA (circRNA) as a delivery vector the editing efficiency has been increased by over 82 %, without experimental evidence of off-target effects. Taking advantage of these gains in technology, these mouse models of mitochondrial diseases, including those associated with Leigh syndrome and LHN, are highly faithful. These models have also confirmed that these specific mtDNA variants have pathological phenotypic evaluations, and have compared to previous editing strategies, mitoBEs v2 have demonstrated improved specificity, stability and safety. We finally discuss the future of mitochondrial base editing and outline the ways it will move forward towards therapeutic potentials in the treatment of the mitochondrial disorders and also in precision medicine.
In silico analysis of a MicroRNA regulatory network Influencing mitochondrial fission in hepatocellular carcinoma.
Akki AJ, Patil SV, Dongre N … +1 more , Parvatikar P
Mitochondrion · 2026 Jan · PMID 41167445 · Publisher ↗
MicroRNAs (miRNAs), small non-coding RNA molecules known for their gene regulatory functions, are increasingly recognized to target genes critical for mitochondrial function in hepatocellular carcinoma (HCC). By employin...
MicroRNAs (miRNAs), small non-coding RNA molecules known for their gene regulatory functions, are increasingly recognized to target genes critical for mitochondrial function in hepatocellular carcinoma (HCC). By employing in silico analysis this research investigates the underexplored involvement of a network of microRNAs in regulating mitochondrial fission within the context of HCC. We constructed a novel regulatory network, identifying hsa-miR-138-5p as a central regulator targeting key mitochondrial genes. Furthermore, we identified druggable binding pockets on the transcription factors WDR5 and HNF4, which regulate hsa-miR-138-5p. Molecular docking studies demonstrated favorable binding affinities of FDA-approved HCC drugs (sorafenib, lenvatinib, and regorafenib) to these binding pockets, suggesting an off-target mechanism by which these drugs might influence mitochondrial function through the hsa-miR-138-5p pathway. These findings contribute to the growing understanding of miRNA-mediated regulation in HCC and offer a foundation for developing novel microRNA-targeting drugs to modulate mitochondrial dynamics to manage HCC progression.
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