Mitochondrion[JOURNAL]
Sun
200 papers
Targeting mitochondrial quality control for myocardial ischemia-reperfusion injury.
He Y, Ren S, Liu C … +2 more , Zheng X, Zhu C
Mitochondrion · 2025 Sep · PMID 40419068 · Publisher ↗
Cardiovascular disease (CVD) remains the leading global cause of mortality. Acute myocardial infarction (AMI) refers to acute myocardial ischemia resulting from thrombosis secondary to coronary atherosclerosis, which pos...
Cardiovascular disease (CVD) remains the leading global cause of mortality. Acute myocardial infarction (AMI) refers to acute myocardial ischemia resulting from thrombosis secondary to coronary atherosclerosis, which poses a major threat to human health. Clinically, timely revascularization (reperfusion) represents the basis of clinical treatment for AMI. However, secondary myocardial ischemia-reperfusion injury (MIRI) caused by reperfusion often exacerbates damage, representing a major challenge in clinical practice. Mitochondria represent essential organelles for maintaining cardiac function and cellular bioenergetics in MIRI. In recent years, the role of mitochondrial quality control (MQC) in maintaining cell homeostasis and mediating MIRI has been extensively studied. This review provides a concise overview of MQC mechanisms at the molecular, organelle, and cellular levels and their possible complex regulatory network in MIRI. In addition, potential treatment strategies targeting MQC to mitigate MIRI are summarized, highlighting the gap between current preclinical research and clinical transformation. Overall, this review provides theoretical guidance for further research and clinical translational studies.
Auditory neuropathy spectrum disorder and related auditory features in patients with hearing loss associated with the MT-TS1 m.7471dup variant.
Minami S, Kida A, Inoue S … +9 more , Murakami H, Morita N, Takagi A, Usui T, Sugiuchi T, Yamazawa K, Nara K, Mutai H, Matsunaga T
Mitochondrion · 2025 Sep · PMID 40404036 · Publisher ↗
The m.7471dup variant of mitochondrial-tRNA Ser (UCN) (MT-TS1) is associated with sensorineural hearing loss (SNHL), neurological abnormalities, or both. Phenotypic variations in SNHL associated with the m.7471dup varian...
The m.7471dup variant of mitochondrial-tRNA Ser (UCN) (MT-TS1) is associated with sensorineural hearing loss (SNHL), neurological abnormalities, or both. Phenotypic variations in SNHL associated with the m.7471dup variant were the focus of our investigation. Five Japanese families carrying the variant were subjected to comprehensive genetic and clinical evaluations and audiometric testing. Notably, two families presented with auditory neuropathy spectrum disorder (ANSD), and two other families presented with auditory brainstem response thresholds much higher than those expected from the pure-tone audiometry results, which is analogous to ANSD. This is the first study to demonstrate that the m.7471dup variant can be associated with ANSD or similar characteristics. The penetrance of the m.7471dup variant was 71.4 % overall, with 100 % penetrance in cases with homoplasmy and 42.9 % penetrance in cases with heteroplasmy. Disease onset was congenital or early onset (≤ 6 years) in 80 % of the patients. The hearing levels ranged from normal to profound, and four subjects presented with neurological or psychiatric abnormalities. About 80 % of subjects who had newborn hearing screening passed the screening, suggesting late-onset or progressive hearing loss. These findings underscore the importance of rigorous follow-up evaluations, genetic counseling, and evaluation of educational environment considerations for patients carrying the m.7471dup variant.
Autologous mitochondrial transplantation enhances the bioenergetics of auditory cells and mitigates cell loss induced by HO.
Okur MN, Ratajczak A, Kheradvar A … +1 more , Djalilian HR
Mitochondrion · 2025 Mar · PMID 40390547 · Full text
Hearing loss is a widespread and disabling condition with no current cure, underscoring the urgent need for new therapeutic approaches for treatment and prevention. A recent mitochondrial therapy approach by introducing...
Hearing loss is a widespread and disabling condition with no current cure, underscoring the urgent need for new therapeutic approaches for treatment and prevention. A recent mitochondrial therapy approach by introducing exogenous mitochondria to the cells has shown promising results in mitigating mitochondria-related disorders. Despite the essential role of mitochondria in hearing, this novel strategy has not yet been tested for the treatment of hearing loss. More importantly, whether cochlear cells take up exogenous mitochondria and its consequence on cell bioenergetics has never been tested before. Here, we showed that exogenous mitochondria from HEI-OC1 auditory cells internalize into a new set of HEI-OC1 cells through co-incubation in a dose-dependent manner without inducing toxicity. We observed that auditory cells that received exogenous mitochondria exhibited increased bioenergetics compared to the controls that received none. Furthermore, we found that mitochondrial transplantation protects cells from oxidative stress and HO-induced apoptosis, while partially restoring bioenergetics diminished by HO exposure. These findings support initial evidence for the feasibility and potential advantages of mitochondrial therapy in auditory cells. If successful in animal models and ultimately in humans, this novel therapy offers prominent potential for the treatment of sensorineural hearing loss.
Corrigendum to "In vitro studies in VCP-associated multisystem proteinopathy suggest altered mitochondrial bioenergetics" [Mitochondrion 22 (2015) 1-8].
Nalbandian A, Llewellyn KJ, Gomez A … +7 more , Walker N, Su H, Dunnigan A, Chwa M, Vesa J, Kenney MC, Kimonis VE
Mitochondrion · 2025 Sep · PMID 40340170 · Publisher ↗
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Urolithin-A supplementation alleviates sepsis-induced acute lung injury by reducing mitochondrial dysfunction and modulating macrophage polarization.
Mohsin M, Zaki A, Tabassum G … +4 more , Khan S, Ali S, Ahmad T, Syed MA
Mitochondrion · 2025 Sep · PMID 40328344 · Publisher ↗
Sepsis is a severe and life-threatening condition marked by excessive inflammation, mitochondrial dysfunction, and epithelial barrier disruption, often leading to Acute Lung Injury (ALI). Mitophagy, a cellular mechanism...
Sepsis is a severe and life-threatening condition marked by excessive inflammation, mitochondrial dysfunction, and epithelial barrier disruption, often leading to Acute Lung Injury (ALI). Mitophagy, a cellular mechanism that removes damaged mitochondria, plays a vital role in maintaining mitochondrial health during sepsis. In this study, we investigated the protective effects of Urolithin-A against ALI and sepsis. In LPS-stimulated RAW264.7 macrophages, Urolithin-A significantly reduced mitochondrial dysfunction, Reactive Oxygen Species (ROS), Nitric Oxide (NO) production, and apoptosis. Additionally, it enhanced mitophagy by upregulating PINK1, Parkin, and LC3-II, which helped preserve mitochondrial function. In vivo, Urolithin-A treatment in mouse models of ALI and sepsis reduced lung injury and inflammation, as shown by improved ALI scores, decreased wet/dry lung weight ratios, and lower levels of inflammatory markers such as iNOS, IL-1β, and MPO. Urolithin-A also improved epithelial barrier integrity and upregulated anti-apoptotic markers, demonstrating its ability to alleviate sepsis-induced lung damage. These findings suggest that Urolithin-A holds significant promise as a therapeutic agent for managing inflammatory lung conditions associated with sepsis.
Exploring the microRNA-mitochondrial nexus in hepatocellular carcinoma.
Akki AJ, Nanduri S, Patil SV … +2 more , Das KK, Parvatikar P
Mitochondrion · 2025 Sep · PMID 40286975 · Publisher ↗
MicroRNAs (miRNAs) are double-edged swords in hepatocellular carcinoma (HCC) that play a dual role in disease progression and suppression. The pivotal role of miRNAs in gene regulation emphasizes their potential to disru...
MicroRNAs (miRNAs) are double-edged swords in hepatocellular carcinoma (HCC) that play a dual role in disease progression and suppression. The pivotal role of miRNAs in gene regulation emphasizes their potential to disrupt critical cellular processes, including mitochondrial function. Given the indispensable role of mitochondria in energy production, apoptosis, and metabolic control, all of which are central to HCC progression, understanding the miRNA-mitochondria axis is crucial. MiRNAs emerge as pivotal regulators of mitochondrial function, exerting profound influence over HCC progression. This comprehensive review delves into the multifaceted roles of miRNAs in modulating mitochondrial biogenesis, dynamics, and apoptosis. MiRNA impacts key metabolic pathways, including energy metabolism, fatty acid metabolism, and oxidative stress. The intricate interplay between miRNAs and mitochondrial function extends to the regulation of mitophagy and ferroptosis. By exploring the microRNA-mitochondrial axis, this review offers insights for identifying novel diagnostic and therapeutic targets.
Mitochondrial transplantation: Triumphs, challenges, and impacts on nuclear genome remodelling.
Shin EH, Le Q, Barboza R … +3 more , Morin A, Singh SM, Castellani CA
Mitochondrion · 2025 Sep · PMID 40254118 · Publisher ↗
Mitochondria are membrane-bound organelles of eukaryotic cells that play crucial roles in cell functioning and homeostasis, including ATP generation for cellular energy. Mitochondrial function is associated with several...
Mitochondria are membrane-bound organelles of eukaryotic cells that play crucial roles in cell functioning and homeostasis, including ATP generation for cellular energy. Mitochondrial function is associated with several complex diseases and disorders, including cardiovascular, cardiometabolic, neurodegenerative diseases and some cancers. The risk for these diseases and disorders is often associated with mitochondrial dysfunction, particularly the quantitative and qualitative features of the mitochondrial genome. Emerging results implicate mito-nuclear crosstalk as the mechanism by which mtDNA variation affects complex disease outcomes. Experimental approaches are emerging for the targeting of mitochondria as a potential therapeutic for several of these diseases, particularly in the form of mitochondrial transplantation. Current approaches to mitochondrial transplantation generally involve isolating healthy mitochondria from donor cells and introducing them to diseased recipients towards amelioration of mitochondrial dysfunction. Using such a protocol, several reports have shown recovery of mitochondrial function and improved disease outcomes post-mitochondrial transplantation, highlighting its potential as a therapeutic method for several complex, severe and debilitating diseases. Additionally, the mitochondrial genome can be modified prior to transplantation to target disease-associated site-specific mutations and to reduce the ratio of mutant-to-WT alleles. These promising results may underlie the potential impact of mitochondrial transplantation on mito-nuclear genome interactions in the setting of the disease. Further, we recommend that mitochondrial transplantation experimentation include an assessment of potential impacts on remodelling of the nuclear genome, particularly the nuclear epigenome and transcriptome. Herein, we review these and other triumphs and challenges of mitochondrial transplantation as a potential novel therapeutic for mitochondria-associated diseases.
Cell-specific mitochondrial response in progressive supranuclear palsy.
Sackmann V, Nassir N, Tanikawa S … +10 more , Forrest SL, Chasiotis H, Li J, Hanif S, Martinez-Valbuena I, Tartaglia MC, Lang AE, Uddin M, Verkhratsky A, Kovacs GG
Mitochondrion · 2025 Sep · PMID 40254117 · Publisher ↗
Progressive supranuclear palsy (PSP) is a main form of idiopathic tauopathy characterized neuropathologically by subcortical neurofibrillary tangles in neurons, oligodendroglial coiled bodies, and tufted astrocytes, whic...
Progressive supranuclear palsy (PSP) is a main form of idiopathic tauopathy characterized neuropathologically by subcortical neurofibrillary tangles in neurons, oligodendroglial coiled bodies, and tufted astrocytes, which follow sequential distribution in the human brain. Mitochondrial dysfunction is thought to be a contributor to many neurodegenerative diseases, but its role in PSP at the cellular level remains incompletely understood. To address this, we performed cell-specific morphometric analysis of mitochondrial markers in post-mortem tissues from motor cortex of PSP patients and non-diseased controls (n = 5 each) followed by single-nuclear transcriptomics (n = 3 each) to identify changes in genes that regulate mitochondrial function. We treated iCell astrocytes with PSP brain homogenates and isolated viable astrocytes from multiple regions of PSP-affected brains. We found that PSP is characterized by significant mitochondrial changes in neurons and astrocytes at the immunohistochemical level, particularly in complex I, with distinct transcriptomic responses across cell types. Glial cells exhibited upregulation of pathways associated with mitochondrial function. In contrast, excitatory and inhibitory neurons showed downregulation in these pathways, indicating impaired mitochondrial function. Astrocytes derived from different human brain regions express varied levels of GFAP and EAAT1 immunoreactivity. Astrocytic tau pathology in cell culture derived from postmortem PSP brains mirrors that seen in corresponding brain tissue histology. Tau pathology in human astrocyte cell culture is associated with clumps of mitochondria potentially associated with impairment in their neuron supportive function. Our results underscore selective complex I damage and cell-type specific patterns that differentiate PSP from other neurodegenerative diseases.
Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases.
Amador-Martínez I, Aranda-Rivera AK, Martínez-Castañeda MR … +1 more , Pedraza-Chaverri J
Mitochondrion · 2025 Sep · PMID 40252890 · Publisher ↗
Mitochondria are essential organelles for cellular function and have become a broad field of study. In cardio-renal diseases, it has been established that mitochondrial dysfunction is a primary mechanism leading to these...
Mitochondria are essential organelles for cellular function and have become a broad field of study. In cardio-renal diseases, it has been established that mitochondrial dysfunction is a primary mechanism leading to these pathologies. Under stress, mitochondria can develop stress response mechanisms to maintain mitochondrial quality control (MQC) and functions. In contrast, the perturbation of these mechanisms has been associated with the pathogenesis of several diseases. Thus, targeting specific pathways within MQC could offer a therapeutic avenue for protecting mitochondrial integrity. However, the mechanisms related to MQC and mitochondrial stress signaling in the cardio-renal axis have been poorly explored. The primary limitations include the lack of reproducibility in the experimental models of cardio-renal disease, the incomplete knowledge of molecules that generate bidirectional damage, and the temporality of the study models. Therefore, we believe that integration of all of those limitations, along with recent advances in MQC mechanisms (i.e., mitophagy), stress signaling pathways (e.g., integrated stress response, mitochondrial unfolded protein response, and mitochondrial protein import), associated pharmacology, and targeted therapeutic approaches could reveal what the deregulation of these mechanisms is like and provide ideas for generating strategies that seek to avoid the progression of cardio-renal diseases.
MiR-718-mediated inhibition of prohibitin 1 influences mitochondrial dynamics, proliferation, and migration of keratinocytes.
Rani H, Saini N
Mitochondrion · 2025 Sep · PMID 40252889 · Publisher ↗
Keratinocyte hyperproliferation is a key characteristic of psoriasis. Prohibitins (PHB) are known to be associated with keratinocyte proliferation and cell cycle regulation, influenced by mitochondrial processes. The obj...
Keratinocyte hyperproliferation is a key characteristic of psoriasis. Prohibitins (PHB) are known to be associated with keratinocyte proliferation and cell cycle regulation, influenced by mitochondrial processes. The objective of this study was to examine the impact of miR-718 overexpression and downregulation on the various PHB1-mitochondria-driven activities in HaCaT keratinocytes. We demonstrated that PHB1 expression is downregulated through direct targeting by miR-718, which then leads to a reduction in the expression of MFN1, MFN2, and OPA1 in miR-718-transfected cells, as evidenced by western blot analysis. Mitochondrial fusion and DRP1-mediated fission, as indicated by western blot results, were further validated using confocal imaging with CMXRoS labeling, contrasting with the effects of AM-718. JC-1 dye staining results demonstrated the miR-718 overexpression facilitates the mitochondrial membrane depolarization that highlighting the PHB1-OPA1 mediated depolarization. Moreover, OPA1 maintains mitochondrial cristae structure and its dysfunction can trigger cell death. Further PHB1 is known to regulate OPA1 function, alters mitochondrial morphology and significantly influences epithelial cell migration. Herein, our data demonstrated a reduction in keratinocyte proliferation and migration, as evidenced by the CCK assay and wound healing assay, respectively, following 24 h of transfection. Ultimately, our data indicates the potential involvement of miR-718 in the mitochondria-mediated suppression of cell proliferation and migration in HaCaT keratinocytes, likely due to modified mitochondrial processes via PHB1.
Miro1- a key player in β-cell function and mitochondrial dynamics under diabetes mellitus.
Kavyashree S, Harithpriya K, Ramkumar KM
Mitochondrion · 2025 Sep · PMID 40204078 · Publisher ↗
Mitochondrial health is crucial for the survival and function of β-cells, preserving glucose homeostasis and effective insulin production. Miro1, a mitochondrial Rho GTPase1 protein, plays an essential role in maintainin...
Mitochondrial health is crucial for the survival and function of β-cells, preserving glucose homeostasis and effective insulin production. Miro1, a mitochondrial Rho GTPase1 protein, plays an essential role in maintaining thequality of mitochondria by regulating calcium homeostasis and mitophagy. In this review, we aim to explore the dysfunction of Miro1 in type 2 diabetes mellitus (T2DM) and its contribution to impaired Ca signaling, which increases oxidative stress in β-cells. This dysfunction is the hallmark of T2DM pathogenesis, leading to insufficient insulin production and poor glycemic control. Additionally, we discuss the role of Miro1 in modulating insulin secretion and inflammation, highlighting its effect on modulating key signaling cascades in β-cells. Altogether, enhancing Miro1 function and activity could alleviate mitochondrial dysfunction, reducing oxidative stress-mediated damage, and improving pancreatic β-cell survival. Targeting Miro1 with small molecules or gene-editing approaches could provide effective strategies for restoring cell function and insulin secretion in diabetic individuals. Exploring the deeper knowledge of Miro1 functions and interactions could lead to novel therapeutic advances in T2DM management.
Kinetic characterization of respirasomes and free complex I from Yarrowia lipolytica.
García-Cruz G, Esparza-Perusquía M, Cruz-Cárdenas A … +2 more , Cruz-Vilchis D, Flores-Herrera O
Mitochondrion · 2025 Jul · PMID 40180170 · Publisher ↗
The mitochondrion is a highly dynamic organelle capable of adapting to external stimuli and the energetic demands of the cell. As the primary source of cellular ATP, generating approximately 90 % of the total, mitochondr...
The mitochondrion is a highly dynamic organelle capable of adapting to external stimuli and the energetic demands of the cell. As the primary source of cellular ATP, generating approximately 90 % of the total, mitochondrion facilitates the association of respiratory complexes I, III, and IV into supramolecular structures called respirasomes. This supramolecular organization enhances protein density within the mitochondrial inner membrane, enabling homogenous energy production. In this study, we investigate the subunits composition and the kinetic characterization of digitonin-solubilized respirasomes and the free complex I from Yarrowia lipolytica as well as their role in reactive oxygen species (ROS) production. The NADH:DBQ oxido reductase activity of respirasome and free complex I was similar. Respiration by respirasome was inhibited with rotenone, antimycin A, or cyanide, simultaneously to an increase in the ROS production. A value of 1.6 ± 0.2 for the NADH oxidized/oxygen reduced ratio was determined for the respirasome activity. The role of interaction between complexes in the function of the respirasome is discussed.
An inherited mtDNA rearrangement, mimicking a single large-scale deletion, associated with MIDD and a primary cardiological phenotype.
Lopriore P, Legati A, Neuhofer CM … +12 more , Lo Gerfo A, Kopajtich R, Barresi M, Cecchi G, Pavlov M, Izzo R, Montano V, Caligo MA, Berutti R, Mancuso M, Prokisch H, Ghezzi D
Mitochondrion · 2025 Jul · PMID 40164291 · Publisher ↗
AIM: To identify the genetic cause in a previously unsolved pedigree, with mother and two daughters suffering of dilated cardiomyopathy with prevailing arrhythmic burden associated with diabetes mellitus and sensorineura...
AIM: To identify the genetic cause in a previously unsolved pedigree, with mother and two daughters suffering of dilated cardiomyopathy with prevailing arrhythmic burden associated with diabetes mellitus and sensorineural hearing loss, without clear evidence of progressive external ophthalmoplegia. METHODS: Several genetic tests were performed over the years including single-gene sequencing, mitochondrial DNA (mtDNA) sequencing, NGS panel for mitochondrial diseases and cardiomyopathies, clinical exome sequencing and whole exome sequencing. Specific amplifications and long-read NGS were used to evaluate mtDNA structural alterations. RESULTS: By means of whole exome sequencing we found a novel heteroplasmic 12 kb-long single deletion in the mtDNA in all affected family members, confirmed by long-range PCR. However, a deeper investigation by long-read NGS revealed indeed the presence of rearranged mtDNA species, formed by a wild-type plus a deleted molecule. This mtDNA duplication turned out to be inherited in our pedigree and present in all tested specimens. CONCLUSION: While mtDNA single large-scale deletions are generally considered sporadic, few old reports described maternally inherited mtDNA duplication We suggest that mtDNA large rearrangements should be considered as possible disease causes in familial cases with unusual mitochondrial phenotypes. Long-read sequencing is useful for the detection of these variants, particularly mtDNA duplications.
Perceived association of mood and symptom severity in adults with mitochondrial diseases.
Kelly C, Cross M, Junker A … +5 more , Englestad K, Rosales XQ, Hirano M, Trumpff C, Picard M
Mitochondrion · 2025 Sep · PMID 40164290 · Publisher ↗
Individuals with genetic mitochondrial diseases suffer from multisystem symptoms that vary in severity and over time, but the factors influencing disease manifestations are poorly understood. Based upon i) patient and fa...
Individuals with genetic mitochondrial diseases suffer from multisystem symptoms that vary in severity and over time, but the factors influencing disease manifestations are poorly understood. Based upon i) patient and family reports that stressful life events trigger or exacerbate symptoms, ii) biologically plausible pathways whereby psychological states and stress hormones influence mitochondrial energy transformation capacity, and iii) epidemiological literature linking traumatic/stressful life events and multiple neurologic disorders, we hypothesized that mitochondrial disease symptom severity may in part vary with daily mood. To examine patients' perception around potential psycho-biological mechanisms known to operate in other chronic illnesses, we administered the Stress, Health and Emotion Survey (SHES) to 70 adults with self-reported mitochondrial diseases. Participants rated how severe each of their symptom(s) was over the past year, separately for either 'good' (happy, calm) or 'bad' (stress, sad) emotional days. On average, patients reported that most symptoms were better on "good" emotional days (p < 0.0001) and worse on "bad" emotional days (p < 0.0001). Of the 29 symptoms assessed, 27 were associated with daily mood (p < 0.01). Some but not all symptoms were reported to be less or more severe on good and bad days, respectively, including fatigue, exercise intolerance, brain fog, and fine motor coordination (ps < 0.0001). These associative results suggest that on average individuals living with mitochondrial diseases perceive a connection between their mood and symptoms severity. These preliminary findings constitute an initial step towards developing more comprehensive models to understand the psychobiological factors that influence the course of mitochondrial diseases.
Therapeutic potential of DDQ in enhancing mitochondrial health and cognitive function in Late-Onset Alzheimer's disease.
Kshirsagar S, Alvir RV, Pradeepkiran JA … +2 more , Reddy AP, Reddy PH
Mitochondrion · 2025 Jul · PMID 40158867 · Publisher ↗
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, mitochondrial dysfunction, and neuroinflammation. This study evaluates the therapeutic potential of DDQ, a small molecule in th...
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, mitochondrial dysfunction, and neuroinflammation. This study evaluates the therapeutic potential of DDQ, a small molecule in the humanized Abeta knockin (hAbKI) mice that represents late-onset AD. Our findings demonstrate that DDQ treatment significantly improves cognitive performance as assessed through behavioral tests, including the rotarod, open field, Y-maze, and Morris water maze, compared to untreated hAbKI mice. At the molecular level, DDQ promoted mitochondrial biogenesis, as evidenced by enhanced expression of key proteins like PGC1α, NRF1, and TFAM. Additionally, DDQ treatment facilitated mitophagy, as indicated by elevated levels of PINK1 and Parkin, and reduced neuroinflammation, reflected by decreased Iba1 and GFAP levels. Transmission electron microscopy analysis revealed a marked improvement in mitochondrial morphology, with increased mitochondrial length and reduced mitochondrial numbers in DDQ-treated mice. Furthermore, DDQ treatment led to an increase in mitophagic vacuoles, suggesting that it effectively removes dysfunctional mitochondria. Taken together, for the first time, our study results support the potential of DDQ as a promising neuroprotective agent for late-onset AD, addressing mitochondrial dysfunction, neuroinflammation, and cognitive decline. Our study focused on developing small molecules that modulate mitophagy, mitochondrial dynamics and neuroinflammatory pathways for aging, AD and other neurodegenerative disorders.
Loss of PGC-1α causes depot-specific alterations in mitochondrial capacity, ROS handling and adaptive responses to metabolic stress in white adipose tissue.
Gudiksen A, Zhou E, Pedersen L … +4 more , Zaia CA, Wille CE, Eliesen EV, Pilegaard H
Mitochondrion · 2025 Jul · PMID 40157624 · Publisher ↗
White adipose tissue (WAT) delivers lipid-fueled metabolic support to systemic energy expenditure through control of lipolytic and re-esterifying regulatory pathways, facilitated by mitochondrial bioenergetic support. Mi...
White adipose tissue (WAT) delivers lipid-fueled metabolic support to systemic energy expenditure through control of lipolytic and re-esterifying regulatory pathways, facilitated by mitochondrial bioenergetic support. Mitochondria are important sources of reactive oxygen species (ROS) and oxidative damage may potentially derail adipocyte function when mitochondrial homeostasis is challenged by overproduction of ROS. Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α is a transcriptional co-activator that in skeletal muscle plays a central role in mitochondrial biogenesis and function but whether PGC-1α is equally important for mitochondrial function and adaptations in white adipose tissue remains to be fully resolved. The aim of the present study was to characterize the necessity of adipocyte PGC-1α for adaptive regulation of mitochondrial function in distinct white adipose depots. PGC-1α adipose tissue-specific knockout (ATKO) and floxed littermate control mice (CTRL) were subjected to either 24 h of fasting or 48 h of cold exposure. Bioenergetics, ROS handling, basal and adaptive protein responses, markers of protein damage as well as lipid cycling capacity and regulation were characterized in distinct WAT depots. ATKO mice demonstrated impairments in respiration as well as reduced OXPHOS protein content in fed and fasted conditions. Increased ROS emission in tandem with diminished mitochondrial antioxidant defense capacity resulted in increased protein oxidation in ATKO WAT. Adipose tissue PGC-1α knockout also led to changes in regulation of lipolysis and potentially triglyceride reesterification in WAT. In conclusion, PGC-1α regulates adipose tissue mitochondrial respiration and ROS balance as well as lipid cycling during metabolic challenges in a depot specific manner.
Mitochondrial DNA copy number and Alzheimer's disease and Parkinson disease.
Qin P, Chen X, Ma P … +7 more , Li X, Lin Y, Liu X, Liang X, Qin T, Liang J, Ouyang J
Mitochondrion · 2025 Jul · PMID 40157623 · Publisher ↗
INTRODUCTION: A systematic review on the association of mitochondrial DNA copy number (mtDNA-CN) with Alzheimer's disease (AD) and Parkinson disease (PD) is lacking and the causal relationship remains unclear. OBJECTIVE:...
INTRODUCTION: A systematic review on the association of mitochondrial DNA copy number (mtDNA-CN) with Alzheimer's disease (AD) and Parkinson disease (PD) is lacking and the causal relationship remains unclear. OBJECTIVE: We aimed to conduct a systematic review of observational studies on the association of mtDNA-CN with AD and PD and perform a bidirectional 2-sample Mendelian randomization (MR) study to investigate their causal relationships. METHODS: PubMed, Embase, and Web of Science were searched for eligible studies before Jan 2025. The causal links were conducted with inverse-variance weighted (IVW) method as the main analysis. RESULTS: Fourteen case-control and 2 cohort studies investigated the association between mtDNA-CN and AD, with 13 reporting decreased mtDNA-CN associated with increased risk of AD and 3 showing no significant association. All the studies (9 case-control, 1 cross-sectional, 2 cohort studies) observed the relation between mtDNA-CN and PD except for 3 studies reporting no significant association. In MR analysis, genetically predicted mtDNA-CN was not associated with AD and PD, whereas genetically predicted AD (β -0.085, 95 % CI -0.156 to -0.013; P = 0.02) but not PD was associated with mtDNA-CN. Sensitivity and replication analyses showed a stable finding. DISCUSSION: The systematic review found limited observational studies on mtDNA-CN and AD and PD and majority were case-control study. Findings of the bidirectional MR study did not support a causal effect of mtDNA-CN in the development of AD and PD but found that AD can lead to decreased levels of mtDNA-CN, which suggest mtDNA-CN as a potential biomarker of AD.
Beneficial effects of mitophagy enhancers on amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer's disease.
Kshirsagar S, Reddy AP, Reddy PH
Mitochondrion · 2025 Jul · PMID 40157622 · Publisher ↗
The purpose of our study is to investigate the beneficial effects of mitophagy enhancers against mutant amyloid precursor protein (APP) and amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer's d...
The purpose of our study is to investigate the beneficial effects of mitophagy enhancers against mutant amyloid precursor protein (APP) and amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Research spanning over two decades highlights the critical role of mitochondrial dysfunction and synaptic damage in the pathogenesis of both early-onset and late-onset AD. Emerging evidence suggests impaired clearance of damaged mitochondria is an early pathological event in AD, positioning mitophagy enhancers as potential therapeutic candidates. This study determined the optimal doses of four mitophagy enhancers-Urolithin A (UA), actinonin, tomatidine, and nicotinamide riboside (NR)-using immortalized mouse hippocampal (HT22) neurons. HT22 cells were transfected with mutant APP (mAPP) cDNA and treated with the enhancers. The effects were assessed by evaluating mRNA and protein expression levels of genes involved in mitochondrial dynamics, biogenesis, mitophagy, and synaptic function, alongside cell survival and mitochondrial respiration. Mitochondrial morphology was also examined in treated and untreated mAPP-HT22 cells. Results showed that mAPP-HT22 cells exhibited increased mitochondrial fission, reduced fusion, downregulated synaptic and mitophagy-related genes, diminished cell survival, impaired mitochondrial respiration, and excessively fragmented, shortened mitochondria. Treatment with mitophagy enhancers reversed these deficits, restoring mitochondrial and synaptic health. Enhanced cell survival, upregulation of mitochondrial fusion, synaptic, and mitophagy genes, improved mitochondrial structure, and reduced fragmentation were observed. Notably, UA demonstrated the most robust mitigating effects. These findings underscore the therapeutic potential of mitophagy enhancers, particularly UA, as promising candidates to treat mitochondrial and synaptic dysfunctions in AD.
Inhibition of the expression of TRIM63 alleviates ventilator-induced diaphragmatic dysfunction by modulating the PPARα/PGC-1α pathway.
Liu J, Chen Y, Han D … +1 more , Huang M
Mitochondrion · 2025 Jul · PMID 40049543 · Publisher ↗
BACKGROUND: Ventilator-induced diaphragmatic dysfunction (VIDD) significantly affects the prognosis of critically ill patients and has attracted considerable attention. Tripartite motif-containing protein 63 (TRIM63) pla...
BACKGROUND: Ventilator-induced diaphragmatic dysfunction (VIDD) significantly affects the prognosis of critically ill patients and has attracted considerable attention. Tripartite motif-containing protein 63 (TRIM63) plays a pivotal role in muscle protein degradation and muscle mass regulation. Its overexpression is closely associated with VIDD; however, data on the specific effects of TRIM63 on this pathological process remain insufficient. OBJECTIVES: The aim of this study is to elucidate the role of TRIM63 in VIDD and to assess the correlation between the TRIM63-peroxisome proliferator activated receptor α (PPARα)/PPAR gamma coactivator (PGC-1α) pathway and mitochondrial function. METHODS: Specific pathogen-free grade female Wistar rats were divided into four groups: Sham + NS, Sham + MyoMed-205, MV + NS, and MV + MyoMed-205. The inhibitor group received MyoMed-205 to suppress the expression of TRIM63. After the experiment, diaphragmatic contractility, mitochondrial structure and function, oxidative stress levels, autophagy, apoptosis, and the involvement of the PPARα/PGC-1α pathway were evaluated. RESULTS: Our findings indicated that inhibiting TRIM63 prevented mechanical ventilation (MV)-induced diaphragmatic contractile dysfunction and atrophy. Mechanistically, inhibition of the expression of TRIM63 resulted in significant upregulation of the PPARα and PGC-1α expression levels, improved mitochondrial dynamics, enhanced the mitochondrial membrane potential, and reduced mitophagy and apoptosis. Structurally, inhibition of the expression of TRIM63 ameliorated MV-induced mitochondrial fragmentation, fusion, and fission. CONCLUSIONS: The upregulated expression of TRIM63 in VIDD exacerbated mitochondrial damage by inhibiting the PPARα/PGC-1α signaling pathway, leading to increased reactive oxygen species, mitophagy, and apoptosis. Inhibition of the expression of TRIM63 enhanced mitochondrial function, decreased mitophagy and apoptosis, and mitigated VIDD. Thus, TRIM63 may serve as a potential target for the prevention and treatment of VIDD.
Drp1 knockdown aggravates obesity-induced cardiac dysfunction and remodeling.
Wu D, Hu Q, Li H … +3 more , Yin Y, Wang P, Wang W
Mitochondrion · 2025 Jul · PMID 40049542 · Full text
Obesity is an independent risk factor for heart failure with preserved ejection fraction (HFpEF). Dynamin related protein 1 (Drp1) is a key regulator of mitochondrial morphology, bioenergetics and quality control. The ro...
Obesity is an independent risk factor for heart failure with preserved ejection fraction (HFpEF). Dynamin related protein 1 (Drp1) is a key regulator of mitochondrial morphology, bioenergetics and quality control. The role of endogenous Drp1 in obesity induced HFpEF remains largely unknown. Here, adult heterozygous Drp1 floxed (Drp1) mice were bred with αMHC-MerCreMer mice and injected with tamoxifen to induce heterogenous Drp1 knockout (hetCKO) in the heart. Control and hetCKO mice exhibited similar increases in body weight and blood glucose and developed insulin resistance after 18-week high-fat diet (HFD)-fed. HFD had no effect on cardiac contractility but induced diastolic dysfunction, fibrosis, cell death and inflammation in Control and hetCKO mice hearts. Importantly, all these adverse effects were exacerbated in the hearts of hetCKO mice, suggesting aggravated cardiac remodeling and diastolic dysfunction. HFD induced mitochondrial fission was blocked, whereas energy deficiency was exaggerated in hetCKO hearts. These effects were associated with suppressed mitochondrial quality control via mitophagy, and increased apoptosis and oxidative stress. These findings suggest that endogenous Drp1 may play an important role in limiting metabolic stress induced heart dysfunction through regulating mitophagy, oxidative stress, mitochondrial function, apoptosis, and inflammation. Our study provides critical insights into how endogenous Drp1 plays a beneficial role in metabolic stress-induced HFpEF.
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