bims-ripira 2026-02-08 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–02–08
seventeen papers selected by
Martín Lopo

Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.
Clinical and biochemical footprints of primary mitochondrial disorders: proposed nosology.
Mitochondrial transfer: A novel mechanism and promising therapeutic strategy in ageing kidney.
Probability of Mitochondrial DNA heteroplasmy in different tissues from European populations.
Irisin regulates mitochondrial function to support synaptogenesis in the developing hippocampus.
LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
What Peroxisomes (Don't) do to Mitochondria.
Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.
Butyrate extends health and lifespan in mice with mitochondrial deficiency.
Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis.
Time-resolved simultaneous imaging of mitochondrial reactive oxygen species and lysosomal permeabilization to determine organelle-centred cell death.
Mechanisms of microRNA trafficking to mitochondria in the heart.
Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
Bidirectional relationship between mitochondrial dysfunction and dysregulated lipid metabolism in Multiple Sclerosis: potential mechanisms and therapeutic implications.
Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.
Environmental enrichment as a mitochondria-targeting systems strategy across neurodegenerative diseases and retinal dystrophies.

Brain. 2026 Feb 02. pii: awag037. [Epub ahead of print]

Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.

Marton Szabo, Daniel Lagos, Emily Cross, Jack Collier, Rita Horvath.

  Primary mitochondrial diseases (PMDs) affect ∼1 in 4,300 individuals, yet mitochondrial dysfunction is also a hallmark of common inherited and acquired disorders. While advances in genomics now allow molecular diagnosis in 30-60% of mitochondrial diseases, treatment remains largely supportive, leading to progressive disability and early mortality. Despite progress in gene-modifying approaches, no approved therapies exist for the majority of mitochondrial diseases, and none of the recent trials have met their primary endpoints, underlining the urgent need for innovative therapeutic strategies. Patients with PMDs have very variable phenotypes, further complicated by increased susceptibility to infections, chronic inflammation and metabolic abnormalities. Recently, it has become evident that certain mitochondrial pathologies, including the loss of mitochondrial membrane integrity, impaired mtDNA maintenance, quality control defects, or respiratory chain defects, result in the release of mtDNA into the cytosol. Infections or metabolic changes also trigger the release of mtDNA, leading to the activation of a sterile innate immune response and interferon signalling. Free mtDNA acts as a pathogen-associated molecular pattern (PAMP), activating innate immune pathways such as the cGAS-STING axis, initiating a sterile inflammatory response. This can be followed by the extracellular release of mtDNA to convey the inflammatory response systemically to communicate between cells or across organs. However, it is unclear whether these pathways worsen the disease phenotype (hyperinflammatory reaction) or, in contrast, rescue the symptoms due to upregulation of compensatory pathways. In this review, we summarise recent advances in understanding the mechanism of mtDNA release and how it activates innate immune signalling in PMDs. We also discuss the implications for pathogenesis, clinical phenotypes, and therapeutic development. Defining the role of circulating mitochondrial material as a biomarker or therapeutic target is a critical step for precision medicine approaches in PMDs. These pathways may also have wider implications for common metabolic, inflammatory, and neurodegenerative disorders with mitochondrial dysfunction.

Keywords:  mitochondria derived vesicles (MDVs); mtDNA; mtDNA release, primary mitochondrial diseases (PMD); pathogen-associated molecular patterns (PAMPs); sterile-inflammation

DOI:  https://doi.org/10.1093/brain/awag037
JCI Insight. 2026 Jan 29. pii: e195170. [Epub ahead of print]

Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.

Natalia W Fluder, Morgane Humbel, Emeline Recazens, Alexis A Jourdain, Camillo Ribi, George C Tsokos, Denis Comte.

  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. Natural killer (NK) cells display marked functional impairment in SLE, including defective cytotoxicity and cytokine production, but the underlying mechanisms remain poorly defined. Here, we show that mitochondrial dysfunction and impaired mitophagy are key contributors to NK cell abnormalities in SLE. Using complementary structural, metabolic, and proteomic analyses, we found that SLE NK cells accumulate enlarged and dysfunctional mitochondria, exhibit impaired lysosomal acidification, and release mitochondrial DNA into the cytosol-features consistent with defective mitochondrial quality control. Transcriptional and proteomic profiling revealed downregulation of key mitophagy-related genes and pathways. These abnormalities correlated with reduced NK cell degranulation and cytokine production. We then tested whether enhancing mitochondrial quality control could restore NK cell function. The mitophagy activator Urolithin A improved mitochondrial and lysosomal parameters and rescued NK cell effector responses in vitro. Hydroxychloroquine partially restored mitochondrial recycling and reduced cytosolic mtDNA. These findings suggest that defective mitophagy and mitochondrial dysfunction are major contributors to NK cell impairment in SLE and that targeting mitochondrial quality control may represent a promising strategy for restoring immune balance in this disease.

Keywords:  Autoimmune diseases; Autoimmunity; Immunology; Lupus; NK cells

DOI:  https://doi.org/10.1172/jci.insight.195170
Mol Genet Metab. 2025 Dec 11. pii: S1096-7192(25)00696-1. [Epub ahead of print]147(3): 109704

Clinical and biochemical footprints of primary mitochondrial disorders: proposed nosology.

Martina Messina, Rebecca Ganetzky, Carlos R Ferreira, Nenad Blau, Shamima Rahman.

  Primary mitochondrial diseases (PMD) are a growing number of disorders caused by mitochondrial dysfunction. There is not yet a consensus on the precise definition of PMD. Therefore, this study presents an approach to developing a nosology for standardized, systematic classification of PMD, harmonized with ICIMD and IEMbase. A total of 452 PMD causative genes were included. The classification includes 18 categories: 1) Disorders of amino acid metabolism; 2) Disorders of peptide and amine metabolism; 3) Disorders of carbohydrate metabolism; 4) Disorders of fatty acid and ketone body metabolism; 5) Disorders of energy substrate metabolism; 6) Mitochondrial DNA-related disorders; 7) Nuclear-encoded disorders of oxidative phosphorylation; 8) Disorders of mitochondrial cofactor biosynthesis; 9) Disorders of mitochondrial DNA maintenance and replication; 10) Disorders of mitochondrial gene expression; 11) Other disorders of mitochondrial function; 12) Disorders of metabolite repair/proofreading; 13) Disorders of lipid metabolism; 14) Disorders of nucleobase, nucleotide and nucleic acid metabolism; 15) Disorders of tetrapyrrole metabolism; 16) Disorders of organelle biogenesis, dynamics and interaction; 17) Disorders of vitamin and cofactor metabolism and 18) Neurotransmitter disorders. We also describe the clinical involvement of 22 organs and systems and laboratory features. The most prevalent symptoms (per gene) were neurological (21.1%), ocular (10.3%), muscular (9.0%), gastrointestinal (8.3%), and cardiovascular (7.9%).

Keywords:  Biomarkers; ICIMD; IEMbase; Inherited metabolic disorders; Signs and symptoms

DOI:  https://doi.org/10.1016/j.ymgme.2025.109704
Ageing Res Rev. 2026 Feb 03. pii: S1568-1637(26)00043-7. [Epub ahead of print] 103051

Mitochondrial transfer: A novel mechanism and promising therapeutic strategy in ageing kidney.

Jingge Xu, Xingyi Li, Zhiyu Zhang, Jiahui Wu, Haiyang Yu, Yuzheng Wu, Dan Wang, Ruixia Bao, Tao Wang, Yi Zhang, Qian Chen.

  As a metabolically active organ, kidney has to challenge progressive functional decline with ageing. Meantime, in the pathogenesis of kidney diseases, renal dysfunction also accelerates an individual's ageing trajectory, leading to premature senescence and a disconnect between biological age and chronological age. Mitochondrial dysfunction is a well-recognized characteristic of kidney ageing, whereas preserving mitochondrial homeostasis can effectively delay the ageing process. This review summarizes classical alterations in mitochondrial function across renal health and disease, including impaired biogenesis with peroxisome proliferator's-activated receptor γ coactivator α (PGC-1α) suppression, fission-fusion imbalance with overactivation of dynamin-related protein 1 (DRP1), mitophagy defects linked to abnormalities in the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway, oxidative stress cascades featuring mitochondrial reactive oxygen species (mtROS)-mediated damage, and dysregulation of mitochondrial protein quality control. Moreover, we critically evaluate mitochondrial transfer as novel, non-canonical pathways beyond classical bioenergetics, generally through tunneling nanotubes (TNTs)/ extracellular vesicle-containing mitochondria (EVMs)/ free mitochondrial, and inter-organelle communication. We also discuss alternative mitochondria-targeted therapeutics and dissect their clinical translation hurdles. Appropriate interventions on mitochondrial transfer represents a promising strategy for preventing kidney ageing to maintain long-term renal health and extend lifespan. However, the majority of the studies we reviewed are based on animal and cellular models of other diseases, the relationship between renal ageing and mitochondrial transfer has not been adequately explored in clinical trials, and there is still a long way to go.

Keywords:  Ageing kidney; Mitochondrial donor cells; Mitochondrial homeostasis; Mitochondrial transfer; Pharmacological therapeutics

DOI:  https://doi.org/10.1016/j.arr.2026.103051
Mitochondrion. 2026 Feb 04. pii: S1567-7249(26)00007-3. [Epub ahead of print]88 102117

Probability of Mitochondrial DNA heteroplasmy in different tissues from European populations.

Daniel R Cuesta-Aguirre, Ana Onieva, M Pilar Aluja, Cristina Santos.

  Mitochondrial DNA (mtDNA) heteroplasmy complicates genetic analyses due to its variability across individuals and tissues. We analyzed over 400 Spanish blood samples and integrated published Massively Parallel Sequencing (MPS) data from ten additional European tissues. Heteroplasmy was tissue-specific, with skeletal muscle, kidney, and liver showing the highest levels, while the intestines, skin, and cerebellum had the lowest. Blood uniquely displayed more heteroplasmies in coding than non-coding regions. Several conserved positions not previously described as hotspots showed high frequencies. These results establish the first comprehensive tissue-specific heteroplasmic profile of the complete mitochondrial genome in a European population, improving the interpretation of mtDNA variation in forensic and biomedical contexts.

Keywords:  Heteroplasmic profile; Heteroplasmy; Massively Parallel Sequencing (MPS); Mitochondrial DNA (mtDNA); Point heteroplasmy

DOI:  https://doi.org/10.1016/j.mito.2026.102117
Mol Cell Neurosci. 2026 Feb 01. pii: S1044-7431(26)00003-5. [Epub ahead of print] 104073

Irisin regulates mitochondrial function to support synaptogenesis in the developing hippocampus.

Mary R Josten, Kyra N Parker, Crystal Dillon, Heiko Jansen, Gary A Wayman.

  Hippocampal synapse proliferation is a critical period in brain development that demands vast supplies of chemical energy. Maternally derived hormones exert vital effects on mitochondrial function in the developing brain, thus determining neuronal synapse proliferative capacity. Here we investigated the mechanisms by which irisin, through the neuronal uncoupling proteins (UCPs) UCP2, UCP4, and UCP5, regulates mitochondrial function to facilitate the growth and maturation of dendritic spines in developing hippocampal neurons. Irisin treatment increased mitochondrial respiration and mitochondrial membrane potential, but not reactive oxygen species production in an in vitro model of developing hippocampal neurons. Irisin treatment also increased the expression of UCP2, UCP4, and UCP5. Knockdown of UCP2, UCP4, and UCP5 exerted differential effects on basal and irisin-stimulated phenotypes in cultured neurons, while overexpression of UCP2, UCP4, or UCP5 exerted differential effects on basal mitochondrial membrane potential, reactive oxygen species levels, and synaptogenesis. Together, these data suggest a role for irisin in regulating neuronal mitochondrial function through a UCP-dependent mechanism to support synaptogenesis during hippocampal development.

Keywords:  Irisin; Mitochondria; Synaptogenesis; Uncoupling proteins

DOI:  https://doi.org/10.1016/j.mcn.2026.104073
bioRxiv. 2026 Jan 15. pii: 2026.01.14.699555. [Epub ahead of print]

LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.

Levi Ali, Avijit Mallick, Yunguang Du, Rui Li, Lihua Julie Zhu, Kuang Shen, Cole M Haynes.

Mitochondrial homeostasis is maintained by multiple molecular chaperones and proteases located within the organelle. The mitochondrial matrix-localized protease LONP-1 degrades oxidatively damaged or misfolded proteins. Importantly, LONP-1 also regulates mitochondrial DNA replication. Here, we show that mutations in C. elegans that impair LONP-1 function cause dysregulation of mitochondrial DNA replication, mitochondrial RNA transcription and protein synthesis within the mitochondrial matrix. LONP-1 deficient worms had reduced levels of oxidative phosphorylation proteins despite increased mtDNA-encoded protein synthesis. Via a forward genetic screen, we identified three mutations that restored mitochondrial function and the rate of development in lonp-1 mutants to levels comparable to those in wildtype worms. Interestingly, all three suppressor mutations were found in genes encoding mitochondrial ribosome proteins. A point mutation in the mitochondrial ribosome protein MRPS-38 restored oxidative phosphorylation in lonp-1 mutant worms. Combined, our results suggest that LONP-1 regulates mitochondrial protein synthesis and that the suppressor mutations within MRPS-38 or MRPS-15 enhance oxidative phosphorylation complex assembly by slowing translation.

DOI: https://doi.org/10.64898/2026.01.14.699555
Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564251413010

What Peroxisomes (Don't) do to Mitochondria.

Margret H Bülow, Sven Thoms.

  Mitochondria and peroxisomes have long been recognized as interconnected. More than half a century ago it was observed that both types of cell organelles exhibit defects in peroxisome biogenesis disorders. Remarkably, until today, the molecular basis of this connection remains elusive. This Short Review aims to highlight some of the functional links between peroxisomes and mitochondria, and how genetic defects in peroxisomes may impact mitochondria.

Keywords:  membrane contact sites; mitochondria; peroxisomes; plasmalogens; reactive oxygen species; zellweger syndrome

DOI:  https://doi.org/10.1177/25152564251413010
bioRxiv. 2026 Jan 14. pii: 2026.01.13.699119. [Epub ahead of print]

Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.

Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.

Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced aged, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in (i) aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control, and (ii) in human primary myotubes. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. In the cell model, ROS and glutathione was measured using luminescent assays. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. In the cell model, B12 supplementation reduced ROS levels. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.

DOI: https://doi.org/10.64898/2026.01.13.699119
bioRxiv. 2026 Jan 14. pii: 2026.01.13.699287. [Epub ahead of print]

Butyrate extends health and lifespan in mice with mitochondrial deficiency.

Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.

Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. To investigate novel strategies that alleviate mitochondrial dysfunction, we have generated an ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfam fl/fl Ub Cre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share deficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.

DOI: https://doi.org/10.64898/2026.01.13.699287
Neurobiol Aging. 2026 Jan 27. pii: S0197-4580(26)00012-6. [Epub ahead of print]161 47-63

Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis.

Zahra Motamed, Gisela Novack, Daniel Heutschi, Carine Gaiser, Corina Garcia, Sonia Do Carmo, A Claudio Cuello, Laura Morelli, Laura Suter-Dick.

  Mitochondrial dysfunction is a well-established hallmark of Alzheimer's disease (AD), particularly in the context of amyloid-beta (Aβ) accumulation. Here, we explored the progression of mitochondrial impairment associated with cerebral amyloidosis in human and rodent systems expressing AD-relevant APP mutations. We investigated mitochondrial function, dynamics, and degradation in human neural progenitor cells differentiated for two and six weeks, carrying the APP (Swedish/London) mutations. These analyses were complemented by studies in 3- and 9-month-old McGill-R-Thy1-APP transgenic (Tg) rats expressing the APP (Swedish/Indiana) mutations. We observed a consistent accumulation of pathogenic Aβ species associated with mitochondrial damage. In vitro, early indicators of oxidative stress and initial alterations in mitochondrial network dynamics were evident, including increased mitochondrial reactive oxygen species and elevated total DRP1 levels. Later, after 6 weeks of differentiation, significant mitochondrial dysfunction emerged, including reduced membrane potential, increased mitochondrial network fragmentation, and decreased GSH/GSSG ratio. Mitophagy was also disrupted, as evidenced by reduced localization of TOMM20 to the lysosomes, suggesting impaired mitochondrial clearance. Similarly, hippocampal mitochondria fraction of 9-month-old Tg rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation, which were absent in 3-month-old Tg animals. Hence, we identified both early and late molecular alterations in mitochondrial homeostasis revealing accumulation of mitochondrial stress, altered dynamics, and mitophagy failure in response to sustained Aβ release. Our results underscore mitochondrial vulnerability during early amyloidosis, identifying it as a potential therapeutic target at initial disease stages. It also reinforces the utility of in vitro models for studying cerebral amyloid pathologies.

Keywords:  APP mutations; Alzheimer´s disease; Amyloid beta; Amyloidosis; Mitochondrial impairment; Mitophagy

DOI:  https://doi.org/10.1016/j.neurobiolaging.2026.01.006
Redox Rep. 2026 Dec;31(1): 2621497

Time-resolved simultaneous imaging of mitochondrial reactive oxygen species and lysosomal permeabilization to determine organelle-centred cell death.

P J Jain Tiffee, Aswathy Sivasailam, Kiran S Kumar, Shine Varghese Jancy, Aparna Geetha Jayaprasad, Aman Munirpasha Halikar, Aijaz Ahmed Rather, Nithin Satheesan Sinivirgin, K G Anurup, T R Santhoshkumar.

   BACKGROUND: Mitochondria and lysosomes are pivotal in dictating cell survival or death outcomes. While mitochondrial damage and ROS production are key events in mitochondrial cell death, lysosome membrane permeabilization and cathepsin B release mark lysosomal cell death. We aimed to generate a live-cell approach to concurrently monitor mitochondrial redox alterations and lysosomal permeabilization. This would provide mechanistic insight into their dynamic interplay during cell death and enable the discovery of organelle-specific death inducers.
METHODS: A dual cell sensor, stably expressing tdTomato-CathepsinB and mitochondria-targeted redox GFP (mt-roGFP), was successfully engineered, and simultaneous imaging of both events by real-time confocal imaging was carried out with selected drugs.
RESULTS: This platform faithfully reported the chronological sequence of organelle-specific events with the progression of cell death, with good temporal and spatial resolution at the single-cell level. Moreover, we have identified and categorised potential lead compounds that predominantly induce lysosomal cell death or mitochondrial cell death, as well as a subset that elicit both events concomitantly.
CONCLUSION: The study provided evidence that both organelles contribute to cell death in a context-dependent manner, and the temporal analysis of both events is critical in understanding unique organelle-centred cell death.

Keywords:  Lysosomal membrane permeabilization; bax activation; cathepsin B; high-throughput drug screening; live cell imaging; live cell sensor; mito-roGFP; mitochondrial oxidation

DOI:  https://doi.org/10.1080/13510002.2026.2621497
Curr Opin Physiol. 2025 Sep;pii: 100848. [Epub ahead of print]45

Mechanisms of microRNA trafficking to mitochondria in the heart.

Diego Quiroga, Rachel Daniel, Samarjit Das.

MicroRNAs (miRNAs) are essential post-transcriptional regulators of gene expression, and accumulating evidence supports their presence and function within mitochondria. These mitochondrial microRNAs (MitomiRs) modulate key processes such as oxidative phosphorylation, ATP production, calcium homeostasis, and reactive oxygen species balance in cardiac tissue. Despite growing recognition of their importance, the mechanisms governing miRNA trafficking to mitochondria remain incompletely understood. This review explores the current knowledge on miRNA biogenesis, mitochondrial import pathways - including the roles of Argonaute 2 (AGO2), the Translocase of the Outer/Inner Mitochondrial Membrane (TOM/TIM) complexes, and Polynucleotide Phosphorylase (PNPase) - and the regulatory impact of specific MitomiRs, such as miR-181c, miR-210, miR-378, let-7b, and miR-1. Understanding how these molecules influence mitochondrial function provides insight into their therapeutic potential in cardiovascular disease.

DOI: https://doi.org/10.1016/j.cophys.2025.100848
bioRxiv. 2026 Jan 25. pii: 2026.01.25.701366. [Epub ahead of print]

Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.

Noe Baruch-Torres, Joon Park, Josue Mora-Garduño, Arkanil Roy, Anupam Singh, G Andrés Cisneros, Luis G Brieba, Smita S Patel, Y Whitney Yin.

Accurate replication of mitochondrial genome (mtDNA) integrity, which is essential for cellular metabolism and energy supply, relies primarily on DNA polymerase gamma (Pol γ), Twinkle helicase, and mitochondrial single-stranded DNA binding protein (mtSSB). Twinkle alone exhibits little helicase activity while reports indicate that Pol γ displays from modest to limited unwinding activity. This led us to dissect Pol γ strand displacement activity using structural, biochemical and in silico approaches. Here, we show that human Pol γ carries out robust strand displacement synthesis at physiological concentrations of divalent metal ions which reveals that distinct metal-binding sites can independently regulate DNA synthesis and unwinding activities. We further showed that Pol γ can displace RNA/DNA hybrid with comparable efficiency as DNA/DNA duplex, representing a key implication on RNA primer removal to preserve mtDNA integrity. Our cryo-electron microscopy structures of Pol γ complexed with a template containing downstream dsDNA and an incoming nucleotide revealed the structural mechanism for the strand displacement activity. We identified four conformational states that represent successive stages of DNA unwinding, accompanied by coordinated rearrangement of the downstream DNA and Pol γ elements that mediate strand displacement. This work establishes biochemical and structural mechanisms of Pol γ strand displacement activity, providing fundamental insight into human mitochondrial DNA replication and integrity.
Graphical abstract:

DOI: https://doi.org/10.64898/2026.01.25.701366
Neurobiol Dis. 2025 Dec;pii: S0969-9961(25)00376-6. [Epub ahead of print]217 107159

Bidirectional relationship between mitochondrial dysfunction and dysregulated lipid metabolism in Multiple Sclerosis: potential mechanisms and therapeutic implications.

Tian Xie, Ho Tin Fok, Zehao Quan, Chun-Yuan Ku, Isaac Oluwatobi Akefe, Daniel Schweitzer.

   BACKGROUND: Multiple Sclerosis (MS) is a heterogeneous neuroinflammatory disease with complex aetiology and diverse clinical presentations, often accompanied by neurodegenerative pathology. While current therapies primarily focus on immunomodulation, emerging evidence underscores a critical bidirectional interplay between mitochondrial dysfunction and lipid dysregulation in driving MS progression. Understanding this metabolic-mitochondrial axis may reveal novel therapeutic opportunities beyond immune modulation.
OBJECTIVE: This scoping review systematically maps recent literature (2015-2025) to delineate the mechanistic connections between mitochondrial dysfunction and lipid dysregulation in MS, identify current knowledge gaps, and highlight translational opportunities for targeted intervention.
METHODS: A systematic search of PubMed, Embase, and Scopus was conducted in 2025 following PRISMA-ScR guidelines. Thirty-six eligible studies examining mitochondrial-lipid interactions in human MS and preclinical models were included and synthesised thematically.
RESULTS: Evidence converges on a self-reinforcing pathological cycle in MS, where dysregulated lipid metabolism impairs mitochondrial integrity, amplifying reactive oxygen species generation, energy failure, and further lipid disruption. This cascade contributes to oligodendrocyte injury, demyelination, ferroptosis, and axonal degeneration. Importantly, therapeutic strategies that restore lipid-mitochondrial homeostasis, such as mitochondrial antioxidants, lipid modulators, and metabolically active immunotherapies, demonstrate promising neuroprotective effects in preclinical studies.
CONCLUSION: The evidence supports a model in which the bidirectional feedback loop between mitochondrial dysfunction and lipid dysregulation represents a significant mechanism contributing to neurodegeneration in MS. Clinically, these insights highlight opportunities for earlier diagnosis and more personalised disease management through the integration of lipid-based biomarkers into patient monitoring and treatment selection. Targeting this metabolic axis holds significant promise for developing next-generation disease-modifying therapies to slow disease progression, enhance neuroprotection, and improve functional recovery across different MS subtypes.

Keywords:  Demyelination; Lipid metabolism; Mitochondria; Multiple sclerosis; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1016/j.nbd.2025.107159
Curr Opin Neurol. 2026 Jan 30.

Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.

Fanny Eysert, Gaëlle Deportes, Elodie Delaquaize, Mounia Chami.

   PURPOSE OF REVIEW: Alzheimer's disease (AD) is commonly defined by its hallmark brain pathologies, yet mounting evidence shows that metabolic impairment particularly linked to mitochondrial dysfunction, is a central and systemic feature of the disease. This review highlights consistent abnormalities in mitochondrial function, and turnover (mitophagy) across multiple AD-derived peripheral cells, including skin fibroblasts, lymphocytes, platelets, and peripheral blood mononuclear cells. We also report on potential peripheral AD biomarkers linked to mitochondria dysfunction in AD.
RECENT FINDINGS: Mitochondrial abnormalities in peripheral cells from individuals with AD robustly correlate with disease development. These mitochondrial dysfunctions mostly include reduced respiratory chain activity, increased accumulation of reactive oxygen species (ROS), altered mitochondrial membrane potential, and consequently decreased ATP production. Studies have also identified a complex pattern of mitochondrial hyperactivity and hypoactivity in peripheral cells of AD patients that appears to depend on the stage of AD and whether the disease is sporadic or familial. Furthermore, multiple steps of the mitophagy pathway are disrupted in peripheral cells as AD progresses. Finally, biochemical and proteomic analyses of peripheral fluids further support the loss of mitochondrial homeostasis in AD patients.
SUMMARY: Collectively, the reviewed findings support mitochondrial homeostasis disruption as a core pathophysiological component of AD and a promising target for biomarker development and therapeutic intervention.

Keywords:  Alzheimer's disease; biomarkers; mitochondria; mitophagy; peripheral cells and fluids

DOI:  https://doi.org/10.1097/WCO.0000000000001457
Front Neurosci. 2026 ;20 1744873

Environmental enrichment as a mitochondria-targeting systems strategy across neurodegenerative diseases and retinal dystrophies.

Dario Rusciano, Caterina Gagliano, Alessandro Avitabile, José Fernando Maya-Vetencourt.

  Mitochondrial dysfunction is a central contributor to neurodegenerative disorders affecting both the central nervous system and the retina, where impaired energy metabolism, oxidative stress, and defective cellular resilience converge to drive progressive neuronal loss. Environmental enrichment (EE), a multimodal non-pharmacological paradigm, has emerged as a powerful modulator of brain and retinal plasticity in preclinical models, promoting adaptive responses that support mitochondrial function and neurotrophic signaling. This review synthesizes evidence indicating that EE influences mitochondrial quality control, redox homeostasis, synaptic resilience, and neuroimmune balance across a range of experimental models of neurodegeneration and retinal dystrophy. While these effects converge on shared downstream pathways, important disease-, cell-type-, and context-specific differences exist, and mechanistic generalization across systems requires caution. Human studies remain limited, heterogeneous, and often focused on functional outcomes rather than direct biological endpoints, resulting in modest and variable effect sizes. Rather than proposing EE as a stand-alone therapy, we frame it as a system-level, disease-modifying context that may enhance endogenous protective capacity and potentially complement pharmacological, genetic, or rehabilitative interventions, pending disease-specific validation. Forward-looking perspectives, including digitally mediated and AI-supported EE-inspired approaches, are discussed as conceptual strategies whose biological relevance will depend on future studies integrating functional outcomes with validated molecular and metabolic biomarkers. Together, the available evidence positions EE as a biologically grounded, non-invasive framework for promoting neuro- and retino-protective resilience, while underscoring the need for rigorously designed translational and clinical studies to define its therapeutic boundaries and mechanisms of action.

Keywords:  environmental enrichment; mitochondria; neurodegeneration; neuronal plasticity; oxidative stress; retinal dystrophy; visual system

DOI:  https://doi.org/10.3389/fnins.2026.1744873