bims-ripira 2026-04-19 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–04–19
fifteen papers selected by
Martín Lopo

Therapeutic and mechanistic insights on mitochondrial transplantation in kidney disease.
Pathogenic role of mitochondrial DNA mutations in heart failure: clinical features, mechanisms, and therapeutic prospects.
Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.
Exosome-derived mtDNA disrupts endothelial barrier integrity and accelerates sepsis progression by inducing mitochondrial dysfunction through the PKCδ gene.
Mitochondrial Dysfunction and Immunoinflammatory Remodeling in Heart Failure: Emerging Role of the mtDNA-cGAS/STING Axis and Therapeutic Opportunities.
Cumulative increases in circulating mtDNA as a potential biomarker of brain injury in rugby union: a pilot study.
Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated Vascular Aging in Middle-Age and Older Men With Low Testosterone.
Growth Differentiation Factor 15 and Physical Function Impairment in the SardiNIA Study.
Oleuropein-based olive leaf extract enhances muscle mitochondrial bioenergetics response to moderate - but not maximal - intensity exercise in humans.
Source-Specific Photobiomodulation Regulates Mitochondrial Bioenergetics, Redox Signaling, and Functional Outputs in C2C12 Myoblasts Across Replicative Aging.
Disentangling Intelligence and Consciousness in Human Brain Organoids.
The role of exercise-mediated mitochondrial quality control remodeling in aging.
Association of Mitochondrial DNA Levels in Peripheral Blood Leukocytes With Physical Performance in Older Adults.
Diagnostic Criteria and Management of MELAS and Stroke-Like Episodes: Consensus-Based Statements.
Beyond energy production: targeting mitochondrial biogenesis in aging and cancer with phytochemical intervention.

Nat Rev Nephrol. 2026 Apr 14.

Therapeutic and mechanistic insights on mitochondrial transplantation in kidney disease.

James D McCully, Aybuke Celik, Amish Asthana, Giuseppe Orlando.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are major contributors to global morbidity and mortality, with limited treatment options beyond supportive care. Mitochondrial dysfunction is a shared feature of both conditions, driving impaired energy production, oxidative stress and cell death. Owing to its reliance on oxidative phosphorylation, the kidney is especially vulnerable to ischaemia-reperfusion injury, a leading cause of AKI and a risk factor for long-term loss of kidney function. Persistent mitochondrial damage contributes to the transition from AKI to CKD, and strategies aimed at restoring mitochondrial health, therefore, have therapeutic potential. Here, we focus on mitochondrial transplantation, a therapeutic approach that delivers viable, respiratory-competent mitochondria to injured tissue to support recovery. Mitochondria for transplantation can be isolated from a variety of sources (autologous or allogeneic) without triggering an immune, autoimmune or inflammatory response, or a reaction to damage-associated molecular patterns. Isolated mitochondria can be delivered by intra-arterial injection, and, once in the target organ, they are rapidly integrated into the cells through endocytosis. Mitochondrial transplantation supports the restoration of mitochondrial function and associated signalling pathways, promoting enhanced organ function and cellular viability. Several preclinical studies have demonstrated improved kidney function, reduced inflammation and preserved mitochondrial structure following mitochondrial therapy in models of ischaemia.

DOI: https://doi.org/10.1038/s41581-026-01072-2
Front Cardiovasc Med. 2026 ;13 1781927

Pathogenic role of mitochondrial DNA mutations in heart failure: clinical features, mechanisms, and therapeutic prospects.

Mingyang Ni, Aijia Zheng, Hang Zheng, Wenqing Jia, Yuansheng Wang, Yuqing Peng, Chenguang Yao, Yanhong Wei, Xueli Wang, Sini Kang.

  Heart failure (Heart failure, HF) is a complex clinical syndrome caused by any abnormality in the structure or function of the heart, resulting in impaired ventricular filling or ejection capacity, with mitochondrial dysfunction recognized as one of the key pathological foundations. In recent years, numerous studies have demonstrated that mitochondrial DNA (mtDNA) mutations play a significant role in cardiomyopathy and HF; however, systematic understanding of their modes of action in disease progression remains limited. Most studies have attributed the pathogenic effects of mtDNA mutations to impaired energy metabolism, emphasizing the consequences of defective oxidative phosphorylation and insufficient ATP production on myocardial function. Emerging evidence, however, indicates that mtDNA mutations also contribute to the development and progression of HF by inducing reactive oxygen species accumulation, disrupting mitochondrial structural and dynamic homeostasis, and activating innate immune inflammatory signaling pathways. Furthermore, variations in mtDNA mutation load and heteroplasmy levels constitute an important molecular basis for the diverse clinical phenotypes of HF, although the underlying mechanisms have yet to be systematically integrated. This review comprehensively summarizes the pathogenic mechanisms of cardiac mtDNA mutations and their heteroplasmy in HF, with particular emphasis on the intrinsic links among mitochondrial metabolic reprogramming, oxidative stress, immune activation, and myocardial remodeling, and outlines potential diagnostic and therapeutic strategies based on mitochondrial dysfunction and mtDNA stability.

Keywords:  cardiomyopathy; energy metabolism; heart failure; immune activation; mitochondrial DNA mutations; mitochondrial dysfunction; oxidative stress; therapeutic strategies

DOI:  https://doi.org/10.3389/fcvm.2026.1781927
HGG Adv. 2026 Apr 10. pii: S2666-2477(26)00054-0. [Epub ahead of print] 100614

Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.

Nikki D Russell, Jonathan M Downie, Mark B Bromberg, Stefan M Pulst, Lynn B Jorde.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with multiple genetic causes. Given the strong evidence of mitochondrial dysfunction in ALS, this study aimed to identify genetic contributors to ALS by focusing on genes involved in mitochondrial function. Whole-genome and exome sequencing data from 1,034 ALS cases were analyzed using two distinct computational tools, which ranked candidate genes based on functional relevance to ALS. POLG, the sole mitochondrial DNA polymerase, emerged as a top candidate gene. RNA-seq analysis revealed that among genes upregulated in samples with a POLG variant, there was an enrichment for mitochondrial pathways such as translation, localization, and mitophagy. It also revealed variants in POLG and SOD1, a well-known ALS gene, to be the most enriched in samples with expression profiles of mitochondrial-related genes that differed most from those of unaffected controls. POLG variant carriers also exhibited an increased burden of mitochondrial genome variants, a pattern shared by carriers of variants in other genes involved in mitochondrial DNA maintenance. Additionally, POLG variant carriers had elevated mitochondrial DNA copy number (mtDNA-CN), similar to carriers of variants in mitophagy-related genes, suggesting impaired mitophagy. Together, these findings implicate POLG as an ALS-associated gene and link mitochondrial DNA maintenance defects, altered expression of mitochondrial-related pathways, and impaired mitophagy to ALS etiology.

DOI: https://doi.org/10.1016/j.xhgg.2026.100614
Biochim Biophys Acta Gen Subj. 2026 Jan;pii: S0304-4165(25)00116-3. [Epub ahead of print]1870(1): 130871

Exosome-derived mtDNA disrupts endothelial barrier integrity and accelerates sepsis progression by inducing mitochondrial dysfunction through the PKCδ gene.

Zhiyong Peng, Xiaojuan Cao, Hejun Gao, Cuiling Li, Jinhan Zhang, Youtan Liu.

  Sepsis, a severe inflammatory response to infection, is characterized by complex and rapidly evolving pathophysiology with high mortality. Mitochondrial DNA (mtDNA) in exosomes is a key damage-associated molecular pattern implicated in sepsis; however, its exact role and mechanisms are unclear. This study investigates how exosome-derived mtDNA induces mitochondrial dysfunction via protein kinase C delta (PKCδ), leading to endothelial barrier disruption and the progression of sepsis. Our analysis revealed significantly elevated levels of the mtDNA markers ND2 and D-loop in serum exosomes from sepsis patients compared to healthy controls. These elevated exosomal mtDNA levels correlated with disease severity and showed a positive association with lung injury markers, including SRAGE, SP-D, and CC16. In vitro experiments demonstrated that both isolated mtDNA and exosomes significantly impaired mitochondrial membrane potential, increased reactive oxygen species (ROS) levels, and reduced the oxygen consumption rate (OCR), suggesting the induction of mitochondrial dysfunction. Moreover, mtDNA promoted endothelial cell damage and increased permeability via PKCδ. Crucially, PKCδ knockdown markedly restored mtDNA-induced mitochondrial dysfunction and cellular permeability damage. In conclusion, Exosome-derived mtDNA triggers mitochondrial dysfunction and endothelial barrier disruption via PKCδ, promoting sepsis progression, suggesting potential therapeutic targets.

Keywords:  Exosome; Mitochondrial dysfunction; PKCδ; Sepsis; mtDNA

DOI:  https://doi.org/10.1016/j.bbagen.2025.130871
Pharmacol Res. 2026 Apr 15. pii: S1043-6618(26)00110-6. [Epub ahead of print] 108195

Mitochondrial Dysfunction and Immunoinflammatory Remodeling in Heart Failure: Emerging Role of the mtDNA-cGAS/STING Axis and Therapeutic Opportunities.

Xi Zhang, Xiangchen Xia, Yanmin Zhang, Xiaomin Liu, Xiaoyu Wei, Shichuan Chen, Yuchen Song, Yicheng Chen, Jianzhong Pang, Qiang Xu, Fuyun Jia.

  Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with persistent sterile inflammation emerging as a critical driver of maladaptive cardiac remodeling beyond hemodynamic stress alone. Recent advances have repositioned mitochondria from passive bioenergetic organelles to active immunometabolic signaling hubs. In this context, mitochondrial DNA (mtDNA) leakage during mitochondrial dysfunction acts as a potent damage-associated molecular pattern (DAMP), engaging the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and amplifying inflammatory cascades that accelerate cardiomyocyte loss, fibrosis, and ventricular failure. In this review, we integrate current evidence linking mitochondrial quality control failure-including oxidative stress, metabolic reprogramming, impaired mitophagy, and dysregulated mitochondrial dynamics-to aberrant activation of the mtDNA-cGAS/STING axis in HF. We further highlight how this pathway contributes to pro-inflammatory remodeling of the cardiac immune microenvironment, thereby establishing a self-sustaining immunoinflammatory loop that perpetuates disease progression. Importantly, we discuss emerging pharmacological strategies targeting this axis, ranging from mitochondrial-directed antioxidants and mitophagy enhancers to small-molecule cGAS/STING inhibitors and advanced cardiac-targeted delivery platforms. Collectively, the mtDNA-cGAS/STING pathway represents a unifying and druggable immunometabolic framework in HF, offering promising opportunities for precision anti-inflammatory intervention and therapeutic innovation.

Keywords:  Mitochondrial dysfunction; cGAS/STING pathway; heart failure; immune inflammation; mitochondrial DNA leakage; therapeutic strategies

DOI:  https://doi.org/10.1016/j.phrs.2026.108195
J Sci Med Sport. 2026 Apr 09. pii: S1440-2440(26)00139-8. [Epub ahead of print]

Cumulative increases in circulating mtDNA as a potential biomarker of brain injury in rugby union: a pilot study.

Valentina Selleri, Marco Bazo, Giorgia Sinigaglia, Giada Zanini, Giulia Micheloni, Francesca Coppi, Roberta D'Alisera, Gustavo Savino, Milena Nasi, Marcello Pinti.

   OBJECTIVES: Rugby is a high contact sport that can lead to head contact events, especially in forward players, triggering inflammatory processes. Mitochondrial DNA, released during injury, may act as a proinflammatory signal. This study aimed to assess levels of three mitochondrial DNA forms-mitochondrial (Fraction 1), protein bound (Fraction 2), and naked (Fraction 3) - across a rugby season and correlate them with neuroinflammatory markers, blood parameters, and head impact exposure.
DESIGN: Observational, longitudinal.
METHODS: Thirteen male professional rugby players were monitored across two matches in the 2023-24 season. Blood samples were collected before (T0, T2), immediately after (T1, T3) each match, and one month post season (T4). Mitochondrial DNA levels and integrity were quantified, along with neuroinflammatory markers and pro-inflammatory cytokines, hematochemical parameters, immune receptor expression and monocyte distribution.
RESULTS: Mitochondrial DNA levels increased progressively from T0 to T4, particularly in forward players. Post-match, Fraction 2 and 3 mitochondrial DNA levels were elevated, with a peak at T4. Interleukin-6 and interleukin-8 rose after both matches, while tumor necrosis factor-alpha increased only at T3. Neurofilament light chain levels spiked post-match but normalized afterward. Baseline mitochondrial DNA correlated with several hematological and metabolic markers, and immune cell subsets. Global Positioning System data linked mitochondrial DNA levels with high powered actions and contact intensity, especially in forward players.
CONCLUSIONS: Repeated head impacts in rugby lead to sustained mitochondrial DNA elevation, suggesting its potential as an early biomarker of cell damage and neuroinflammation. This may aid in preventing sports- related neurodegeneration.

Keywords:  Concussions; Head impacts; MtDNA integrity; Neuroinflammation; Professional rugby players; Tackles

DOI:  https://doi.org/10.1016/j.jsams.2026.03.024
Aging Cell. 2026 Apr;25(4): e70457

Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated Vascular Aging in Middle-Age and Older Men With Low Testosterone.

Branden L Nguyen, Mackenzie N Kehmeier, Matthew C Babcock, Lyndsey E DuBose, Kerry L Hildreth, Brian L Stauffer, Ryan Rosenberry, Amy C Keller, Kira Steinke, Kaleb Miles, Lucas Guerrero, Wendy M Kohrt, Jane Reusch, Zachary S Clayton, Kerrie L Moreau.

  Middle-aged/older (MA/O) men with low testosterone have greater oxidative stress-mediated vascular endothelial dysfunction, a major risk factor for cardiovascular disease (CVD). Testosterone deficiency impairs mitochondria, a source and target of oxidative stress. Whether the greater vascular endothelial dysfunction in MA/O men with low testosterone is related to mitochondrial dysfunction is unknown. This cross-sectional study measured mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), and regulators of mitochondrial function (i.e., sirtuins [SIRTs]), and oxidant burden in vascular endothelial cells from (1) young adult men with normal testosterone (18-40 years; serum testosterone ≥ 13.9 nmol/L [400 ng/dL]; n = 23); (2) MA/O men with normal testosterone (50-75 years; serum testosterone ≥ 13.9 nmol/L [400 ng/dL]; n = 57), and (3) MA/O men with low testosterone (50-75 years; serum testosterone < 10.4 nmol/L [300 ng/dL]; n = 21). PBMCs from MA/O men with low testosterone had reduced carbohydrate (2.96 ± 0.65 vs. 6.85 ± 0.77 pmol/s·million cells; p = 0.001) and lipid-supported (4.10 ± 0.67 vs. 6.23 ± 0.69 pmol/s·million cells; p = 0.047) state 2 respiration compared to young men, and lower carbohydrate-supported uncoupled respiration than age-matched men with normal testosterone (17.77 ± 2.91 vs. 24.9 ± 1.93 pmol/s·million cells; p = 0.046). SIRT3 arterial (0.64 ± 0.04 vs. 0.99 ± 0.08 FU; p = 0.003) and venous (0.61 ± 0.03 vs. 0.92 ± 0.07 FU; p = 0.003) expression was lower in endothelial cells from MA/O men with low testosterone compared to age-matched men with normal testosterone. This study highlights the potential role of mitochondrial respiration and regulation in accelerated vascular aging in hypogonadal MA/O men. Importantly, these findings provide promising evidence for clinical therapeutic interventions to target mitochondrial health and SIRT3 to mitigate accelerated vascular aging in hypogonadal MA/O men.

Keywords:  aging; endothelial dysfunction; hypogonadism; mitochondria; sex hormones

DOI:  https://doi.org/10.1111/acel.70457
J Clin Med. 2026 Mar 29. pii: 2612. [Epub ahead of print]15(7):

Growth Differentiation Factor 15 and Physical Function Impairment in the SardiNIA Study.

Nicia I Profili, Edoardo Fiorillo, Valeria Orrù, Maria Benelli, Francesco Cucca, Alessandro P Delitala.

  Background: Sarcopenia is the age-related, progressive loss of strength, function, and skeletal muscle mass, which can be assessed with specific tests. The Growth differentiation factor 15 (GDF-15) has been proposed as a key biomarker of aging, and it has been associated with mitochondrial dysfunction, cachexia, and physical impairment. Methods: The cohort of this study comes from the SardiNIA study, an ongoing longitudinal survey focused on the identification of genetic and phenotypic variants associated with aging. We assessed hand grip strength, gait speed, and GDF-15 in all samples. Linear multivariate analysis was used to assess the correlation after adjusting for a range of potential confounders. Results: The sample consisted of 4842 subjects (57.5% female) with a median age of 48.6 years. Levels of GDF-15 were comparable between males and females and showed a strong positive association with aging (rho 0.617, p < 0.001). Linear multivariate regression analyses showed that GDF-15 was negatively associated with gait speed and grip strength in both hands (respectively, Beta -0.09, Beta -0.07, and Beta -0.08, p < 0.001 for all). Conclusions: GDF-15 was negatively associated with physical function. GDF-15 may be considered a proxy for reduced physical performance. Future research is needed to understand the pathogenetic role of GDF-15 in the reduction in skeletal muscle in aging people.

Keywords:  GDF-15; gait speed; grip strength; mitochondrial dysfunction; reduced physical performance; skeletal muscle

DOI:  https://doi.org/10.3390/jcm15072612
J Physiol. 2026 Apr 14.

Oleuropein-based olive leaf extract enhances muscle mitochondrial bioenergetics response to moderate - but not maximal - intensity exercise in humans.

Clément Lanfranchi, Alba Moreno-Asso, Astrid M H Horstman, Sara Mistro, Eugenia Migliavacca, Ornella Cominetti, Jens Stolte, Sylviane Métairon, Aurélie Hermant, Ane Laura Pedersen, Loïc Dayon, Umberto De Marchi, Jérôme N Feige, Nadège Zanou, Nicolas Place.

  Sprint interval exercise (SIE) induces skeletal muscle mitochondrial adaptations that are comparable to, or greater than, those observed with moderate-intensity continuous exercise (MICE), despite requiring a lower training volume. Previous work has shown that these adaptations are at least partly mediated by enhanced mitochondrial bioenergetics, including increased mitochondrial Ca2+ uptake and resulting pyruvate dehydrogenase (PDH) activation. In parallel, the natural compound oleuropein from olive leaf extract (OLE) promotes mitochondrial Ca2+ uptake and activates PDH in mouse skeletal muscle. Here, we tested the hypothesis that OLE intake would activate PDH and potentiate mitochondrial adaptations in human skeletal muscle during either MICE or SIE. In a crossover, double-blind study, healthy males performed MICE (1 h at 50% maximal aerobic power, n = 11) or SIE (6 × 30 s all-out sprints with 4 min recovery, n = 10). Knee extensor neuromuscular tests and vastus lateralis muscle biopsies were performed before, immediately after and 24 h after SIE or MICE. OLE improved the decline of power output during the first sprint in SIE and reduced heart rate during MICE but did not affect knee extensor fatigability after both exercise modalities. Transcriptomic analyses revealed an effect of OLE on the mitochondrial and inflammatory response after MICE and SIE, while OLE increased PDH activity in combination with exercise only following MICE. Together, these results suggest that OLE modulates skeletal muscle response to exercise and pave the way for future investigations aiming to investigate the chronic effect of combining OLE and exercise training. KEY POINTS: Previous studies have shown that oleuropein increases mitochondrial calcium uptake in preclinical models and that mitochondrial calcium uptake contributes to skeletal muscle mitochondrial adaptations in response to maximal intensity exercise in humans. Olive leaf extract (OLE) increases the activity of pyruvate dehydrogenase, a proxy of mitochondria calcium uptake, when combined with moderate-intensity exercise. Combining moderate-intensity continuous exercise and sprint interval exercise with OLE enhances the mitochondrial response at a transcriptional level. OLE enhances skeletal muscle mitochondrial response to acute exercise, paving the way for investigating its effect in combination with chronic exercise training protocols.

Keywords:  calcium mitochondria; muscle fatigue; oxidative phosphorylation; power output; pyruvate dehydrogenase

DOI:  https://doi.org/10.1113/JP290316
Int J Mol Sci. 2026 Mar 25. pii: 2999. [Epub ahead of print]27(7):

Source-Specific Photobiomodulation Regulates Mitochondrial Bioenergetics, Redox Signaling, and Functional Outputs in C2C12 Myoblasts Across Replicative Aging.

Ana Elena Aviña, Nguyen Le Thanh Hang, Che-Yi Chang, Yi-Fan Chen, Yun Yen, Xavier Pei-Chun Wong, Aline Yen Ling Wang, Cheng-Jen Chang, Tzu-Sen Yang.

  Age-related muscle decline is associated with impaired mitochondrial bioenergetics, altered redox signaling, and reduced myogenic capacity, yet how photobiomodulation (PBM) source characteristics shape these processes under replicative aging remains unclear. Here, we investigated source-specific PBM responses in C2C12 myoblasts using a 660 nm light-emitting diode (LED) and an 830 nm near-infrared (NIR) laser across fluence ranges and replicative stages. Single-cell screening performed at passage 25 identified 5 J/cm2 as the optimal fluence for both sources, producing biphasic increases in mitochondrial membrane potential and ROS. Population-level assays in young (≤5 passages) and old (≥30 passages) cells revealed divergent downstream outcomes. LED irradiation elicited stronger metabolic activation and ATP production, particularly in aged cells, whereas NIR irradiation robustly enhanced myogenic fusion in both age groups and partially rescued differentiation deficits in aged myoblasts. Bulk ROS increased significantly after PBM independent of source, while extracellular vesicle release displayed age-dependent source sensitivity, with NIR favoring canonical small EV populations in young cells and LED inducing greater particle release in aged cells. Together, these findings demonstrate that PBM engages conserved mitochondrial signaling while source-specific delivery and wavelength differentially direct metabolic, paracrine, and myogenic outputs under replicative aging conditions.

Keywords:  C2C12 myoblasts; LED; NIR; aging; bioenergetics; extracellular vesicles; mitochondria; muscle; photobiomodulation; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms27072999
AJOB Neurosci. 2026 Apr-Jun;17(2):17(2): 124-126

Disentangling Intelligence and Consciousness in Human Brain Organoids.

Nada S Salem.

DOI: https://doi.org/10.1080/21507740.2026.2649187
Front Cell Dev Biol. 2026 ;14 1792645

The role of exercise-mediated mitochondrial quality control remodeling in aging.

Tao Cai, Yating Li, Yunsong Zhang, Chunyan Li, Shanhui Li, Qi Zhang.

  Aging is intimately associated with multisystem functional decline and an increased risk of chronic diseases. A pivotal cytological basis underlying this process is the progressive dysregulation of the mitochondrial quality control (MQC) network. Emerging evidence suggests that MQC is not a singular process but rather a multitiered synergistic system encompassing mitochondrial biogenesis, dynamic remodeling, selective autophagy (mitophagy), proteostasis maintenance, and coordinated mitochondrial-organelle communication. This integrated network is critical for preserving cellular energy homeostasis, redox balance, and stress tolerance. During aging, impairments in mitochondrial genomic coordination, network topology, autophagic flux, and protein import and folding collectively contribute to bioenergetic decline, chronic low-grade inflammation, and metabolic imbalance. As a safe and sustainable nonpharmacological intervention, regular exercise systematically remodels MQC structure and function by integrating signaling axes such as AMPK, SIRT1, and p38 MAPK, thereby promoting coordinated mitochondrial renewal and partially reversing aging-associated mitochondrial dysfunction. On the basis of a systematic elucidation of the core mechanisms of MQC and its dysregulation during aging, this review highlights the differential regulatory effects of distinct exercise modalities-specifically endurance training, high-intensity interval training (HIIT), and resistance training-on mitochondrial dynamics, autophagic flux, proteostasis, and mitochondrial turnover. Furthermore, the intrinsic associations among exercise-MQC coupling, inflammatory responses, metabolic imbalances, and emerging peripheral biomarkers are explored. Finally, current research limitations and challenges in clinical translation are analyzed, and future research directions regarding dose-response relationships, multimodal exercise prescriptions, personalized strategies, and systemic integrated regulation are proposed. This review aims to provide a refined theoretical basis for optimizing exercise-based anti-aging interventions.

Keywords:  age; aging; exercise; mitochondrial quality control; physical training

DOI:  https://doi.org/10.3389/fcell.2026.1792645
Geriatr Gerontol Int. 2026 Apr;26(4): e70484

Association of Mitochondrial DNA Levels in Peripheral Blood Leukocytes With Physical Performance in Older Adults.

Hiroaki Ikezaki, Ryoko Nakashima, Hideyuki Nomura, Nobuyuki Shimono.

   BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) in peripheral blood leukocytes has emerged as a surrogate marker of mitochondrial function. This study examined associations between leukocyte mtDNA-CN, physical performance, and lipid metabolism in community-dwelling older adults.
METHODS: We conducted a cross-sectional analysis of 594 adults aged ≥ 50 years (median 71 years; 351 women, 243 men) who were independent in activities of daily living. Physical performance was assessed using handgrip strength and gait parameters measured with a triaxial accelerometer. Frailty status was evaluated using the Japanese version of the Cardiovascular Health Study (J-CHS) criteria. Blood samples were collected after fasting for mtDNA-CN and other blood chemical measurements.
RESULTS: Median values of mtDNA-CN were 124 in women and 114 in men. According to the J-CHS criteria, 6.1% of women and 6.3% of men were classified as frail, while 48.9% of women and 53.6% of men were pre-frail. Participants with higher mtDNA-CN levels demonstrated superior physical performance. After multivariable adjustment, mtDNA-CN correlated positively with gate ability in women and handgrip strength in men. In addition, mtDNA-CN correlated positively with iron in women and high-density lipoprotein cholesterol (HDL-C) in men, and negatively with uric acid and C-reactive protein in men. In the multivariate regression analyses, mtDNA-CN still showed positive associations with handgrip strength and HDL-C, a negative association with uric acid in men, and a positive association with iron in women and men.
CONCLUSION: Leukocyte mtDNA-CN was associated with physical performance, suggesting its potential utility as a biomarker for frailty assessment in older adults.

Keywords:  frailty; gait speed; handgrip; mitochondrial DNA; triglycerides

DOI:  https://doi.org/10.1111/ggi.70484
Eur J Neurol. 2026 Apr;33(4): e70588

Diagnostic Criteria and Management of MELAS and Stroke-Like Episodes: Consensus-Based Statements.

Michelangelo Mancuso, Marcello Bellusci, Valerio Carelli, Irenaeus de Coo, Daria Diodato, Felix Distelmaier, Omar Hikmat, Michio Hirano, Rita Horvath, Amel Karaa, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Chiara La Morgia, Piervito Lopriore, Mika Henrik Martikainen, Robert McFarland, Olimpia Musumeci, Robert D S Pitceathly, Guido Primiano, Shamima Rahman, Fernando Scaglia, Andrew Schaefer, Manuel Schiff, Luisa Semmler, Costanza Lamperti, Serenella Servidei.

   BACKGROUND AND PURPOSE: Mitochondrial Encephalomyopathy, Lactic acidosis and Stroke-like episodes (MELAS) is a rare multisystem mitochondrial disorder with clinical heterogeneity. Diagnostic criteria and management strategies for MELAS and mitochondrial stroke-like episodes (SLE) remain inconsistent. This work provides international consensus recommendations on the definition, diagnosis, and management of MELAS and SLE in pediatric and adult populations.
METHODS: An international Delphi consensus process was conducted within the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD), in collaboration with the US Mitochondrial Medicine Society, the ERN for Hereditary Metabolic Disorders (MetabERN), and patient representatives. Following a systematic literature review, 54 statements addressing diagnostic definitions and management of MELAS were evaluated. Statements not reaching consensus were revised and re-evaluated during a face-to-face meeting.
RESULTS: Consensus supported defining MELAS as a clinical syndrome characterized by one or more SLE in the context of mitochondrial dysfunction caused by a pathogenic mitochondrial DNA variant, particularly m.3243A>G in MT-TL1. The use of terms such as "MELAS-like" or "MELAS spectrum" was discouraged. The panel agreed that the efficacy of L-arginine, L-taurine, L-citrulline, coenzyme Q10, vitamins, and other supplements remains unproven and requires validation in clinical trials. Antiseizure medications should be initiated promptly when seizures are suspected during SLE, and intravenous corticosteroids may be beneficial acutely. Multidisciplinary management of neurological, neuropsychiatric, and systemic complications was endorsed.
CONCLUSIONS: This international consensus provides updated definitions and practical guidance for the diagnosis and management of MELAS and SLE, aiming to harmonize clinical practice and inform future evidence-based research.

Keywords:  MELAS; consensus; diagnostic criteria; management; primary mitochondrial diseases; recommendations

DOI:  https://doi.org/10.1111/ene.70588
Naunyn Schmiedebergs Arch Pharmacol. 2026 Apr 17.

Beyond energy production: targeting mitochondrial biogenesis in aging and cancer with phytochemical intervention.

Adelene Gan-Yin-Xuen, Soni Thakur, Mohd Adnan, Sreenivasan Sasidharan.

  Mitochondrial biogenesis, the process by which cells generate new mitochondria, is crucial for maintaining cellular homeostasis, energy production, and overall health. Mitochondrial dysfunction is a key factor in both aging and cancer, where it contributes to the decline in cellular function and facilitates the progression of disease. In aging, mitochondrial alterations lead to impaired metabolic function, increased oxidative stress, and cellular senescence. Similarly, cancer cells often exhibit altered mitochondrial dynamics, which support rapid proliferation and resistance to apoptosis. Despite their differences, aging and cancer share common molecular mechanisms, particularly in mitochondrial dysregulation, that offer insights into potential therapeutic strategies. Recent research has highlighted the potential of medicinal plants and their bioactive compounds in modulating mitochondrial biogenesis and mitigating dysfunction. Phytochemicals have shown promise in enhancing mitochondrial function, promoting healthy aging, and inhibiting cancer progression. This review explores the molecular mechanisms underlying mitochondrial biogenesis, its dysregulation in aging and cancer, and the therapeutic potential of plant-based compounds in targeting mitochondrial dysfunction. By understanding the intricate relationship between mitochondria, aging, and cancer, novel therapeutic strategies can be developed to improve cellular health and combat age-related diseases and cancer.

Keywords:  Aging; Cancer; Mitochondrial biogenesis; Mitochondrial dysfunction; Phytochemicals

DOI:  https://doi.org/10.1007/s00210-026-05299-5