bims-mitmed 2025-06-01 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–06–01
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Delineating the mechanisms of cerebellar degeneration in paediatric and adult primary mitochondrial disease.
Base editing of trinucleotide repeats that cause Huntington's disease and Friedreich's ataxia reduces somatic repeat expansions in patient cells and in mice.
Immunoproteasome-specific subunit alterations as a potential therapeutic target for mitochondriopathies.
The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.
Exploring the Phenotypic Heterogeneity and Bioenergetic Profile of the m.13513G>A mtDNA Substitution: A Heteroplasmy Perspective.
Cellular Metabolic Disorders in a Cohort of Patients with Sjogren's Disease.
Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.
Infant With a Severe Form of GLRX5-Related Atypical Hyperglycinemia Exhibiting Novel Cardiac and Neurologic Disease Manifestations at Autopsy.
The crossroads of Leber hereditary optic neuropathy and autosomal dominant optic Atrophy: Clinical profiles of patients with coexisting pathogenic genetic variants.
Tissue-specific differences impacts therapeutic outcomes of mitochondrial transplantation through regulation of bioenergetics in metabolic syndrome.
Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
In vivo structure profiling reveals human cytosolic and mitochondrial tRNA structurome and interactome in response to stress.
Cannabinol (CBN) alleviates age-related cognitive decline by improving synaptic and mitochondrial health.
Genetically encoded fluorescent reporter for polyamines.
Deficiency in the conserved ECHS1 gene causes Leigh syndrome by impairing mitochondrial respiration efficiency and suppressing ADRB2-PKA signaling.
Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.
PGC-1 alpha regulates mitochondrial biogenesis to promote silica-induced pulmonary fibrosis.
CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node.
Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy.
MICU1 myopathy revisited: phenotypic variability in a rare mitochondrial calcium disorder.
A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism.

Acta Neuropathol. 2025 May 30. 149(1): 53

Delineating the mechanisms of cerebellar degeneration in paediatric and adult primary mitochondrial disease.

Laura A Smith, Elizaveta A Olkhova, Nichola Z Lax, Yi Shiau Ng, Robert W Taylor, Grainne S Gorman, Daniel Erskine, Robert McFarland.

  Cerebellar ataxia is a frequent, debilitating neurological manifestation of primary mitochondrial disease and is associated with extensive neurodegeneration of the cerebellar cortical circuitry. However, the precise neuropathological mechanisms resulting in cerebellar degeneration in paediatric and adult forms of mitochondrial disease remain unclear. We therefore sought to perform a comparative neuropathological study using post-mortem cerebellar tissues from 28 paediatric and adult patients with pathogenic bi-allelic POLG variants and pathogenic mitochondrial DNA variants (m.3243A > G, m.8344A > G, m.13094T > C, and m.14709T > C), in addition to 18 neurologically normal control cases. We also sought to assess the prevalence and progression of cerebellar ataxia in an adult mitochondrial disease patient clinical cohort (n = 310) harbouring the same pathogenic variants as the post-mortem cases. Analysis of the clinical patient cohort revealed that at least 23.5-39.7% of adult patients with primary mitochondrial disease had predominantly cerebellar ataxia, with disease progression evident in 38.8% of patients. In the mitochondrial disease post-mortem tissue cohort, there was clear evidence of selective loss of inhibitory Purkinje cells, with corresponding oxidative phosphorylation protein deficiencies, which were more severe in comparison to mainly excitatory neuronal populations of the granule cell layer and dentate nucleus. Remaining Purkinje cells also demonstrated an increased expression of mitophagy-related proteins, including LC3B and BNIP3. Focal necrotic cerebellar cortical lesions, identified in eight patients, were characterised by decreased parvalbumin immunoreactivity, and sporadic c-Fos immunoreactivity was observed throughout the cerebellar cortices of 14 patients, suggestive of cerebellar cortical hyperactivity. Overall, these neuropathological features were more severe in the early onset POLG-related disease group and patients who had epilepsy. Our findings provide an important insight to the pathological mechanisms contributing to the degeneration of the cerebellar cortex in paediatric and adult forms of primary mitochondrial disease, highlighting an increased burden of pathology in early onset POLG-related disease which may have important prognostic and therapeutic implications.

Keywords:  Alpers’ syndrome; DNA polymerase gamma (POLG); MELAS; MERRF; Stroke-like episodes; mtDNA

DOI:  https://doi.org/10.1007/s00401-025-02891-6
Nat Genet. 2025 May 26.

Base editing of trinucleotide repeats that cause Huntington's disease and Friedreich's ataxia reduces somatic repeat expansions in patient cells and in mice.

Zaneta Matuszek, Mandana Arbab, Maheswaran Kesavan, Alvin Hsu, Jennie C L Roy, Jing Zhao, Tian Yu, Ben Weisburd, Gregory A Newby, Neil J Doherty, Muzhou Wu, Shota Shibata, Ana Cristian, Y Allen Tao, Liam G Fearnley, Melanie Bahlo, Heidi L Rehm, Jun Xie, Guangping Gao, Ricardo Mouro Pinto, David R Liu.

Trinucleotide repeat (TNR) diseases are neurological disorders caused by expanded genomic TNRs that become unstable in a length-dependent manner. The CAG•CTG sequence is found in approximately one-third of pathogenic TNR loci, including the HTT gene that causes Huntington's disease. Friedreich's ataxia, the most prevalent hereditary ataxia, results from GAA repeat expansion at the FXN gene. Here we used cytosine and adenine base editing to reduce the repetitiveness of TNRs in patient cells and in mice. Base editors introduced G•C>A•T and A•T>G•C interruptions at CAG and GAA repeats, mimicking stable, nonpathogenic alleles that naturally occur in people. AAV9 delivery of optimized base editors in Htt.Q111 Huntington's disease and YG8s Friedreich's ataxia mice resulted in efficient editing in transduced tissues, and significantly reduced repeat expansion in the central nervous system. These findings demonstrate that introducing interruptions in pathogenic TNRs can mitigate a key neurological feature of TNR diseases in vivo.

DOI: https://doi.org/10.1038/s41588-025-02172-8
J Mol Biol. 2025 May 23. pii: S0022-2836(25)00295-5. [Epub ahead of print] 169229

Immunoproteasome-specific subunit alterations as a potential therapeutic target for mitochondriopathies.

Agata Kodroń, Konrad Kowalski, Ben Hur Marins Mussulini, Cem Hazir, Mayra A Borrero-Landazabal, Sonia Ngati, Michal Wasilewski, Agnieszka Chacinska.

  Mitochondria are double-membrane organelles crucial for eukaryotic cells due to their role in ATP production by oxidative phosphorylation (OXPHOS). Most of the ∼1500 proteins of the mitochondrial proteome are encoded in the nuclear genome, synthesized in the cytosol, and actively transported into mitochondria. The proteasome, a major cellular proteolytic machinery, plays an important role in the quality control of their transport by degradation of inefficiently imported mitochondrial proteins in the cytosol. Proteasome inhibition by bortezomib was described as a strategy to alleviate deficiencies stemming from an inefficient import of proteins into the mitochondria. Notably, an impairment of the respiratory complexes was shown to induce a rearrangement of the proteasome composition to incorporate some of the immunoproteasome catalytic subunits, such as PSMB9. In this study, we demonstrated that targeting immunoproteasome inhibited degradation, and thus restored the abundance of inefficiently imported respiratory complex IV proteins in the patient derived fibroblasts. Furthermore, we demonstrated that the immunoproteasome-specific inhibitors displayed a decreased toxicity compared to bortezomib. Our results indicate that immunoproteasome subunits present a novel molecular target for future therapies of mitochondriopathies.

Keywords:  PSMB9; immunoproteasome inhibitors; immunoproteasome subunits; mitochondria; mitochondrial diseases

DOI:  https://doi.org/10.1016/j.jmb.2025.169229
Biol Chem. 2025 May 27.

The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.

Matthias Weith, Konstantin Weiss, Dylan Stobbe, Jan Riemer.

  The mitochondrial intermembrane space (IMS) houses proteins essential for redox regulation, protein import, signaling, and energy metabolism. Protein import into the IMS is mediated by dedicated pathways, including the disulfide relay pathway for oxidative folding. In addition, various IMS-traversing import pathways potentially expose unfolded proteins, representing threats to proteostasis. This trafficking of precursors coincides with unique biophysical challenges in the IMS, including a confined volume, elevated temperature, variable pH and high levels of reactive oxygen species. Ultrastructural properties and import supercomplex formation ameliorate these challenges. Nonetheless, IMS proteostasis requires constant maintenance by chaperones, folding catalysts, and proteases to counteract misfolding and aggregation. The IMS plays a key role in stress signaling, where proteostasis disruptions trigger responses including the integrated stress response (ISR) activated by mitochondrial stress (ISRmt) and responses to cytosolic accumulation of mitochondrial protein precursors. This review explores the biology and mechanisms governing IMS proteostasis, presents models, which have been employed to decipher IMS-specific stress responses, and discusses open questions.

Keywords:  IMS; mitochondria; protein import; proteostasis; stress responses

DOI:  https://doi.org/10.1515/hsz-2025-0108
Int J Mol Sci. 2025 May 10. pii: 4565. [Epub ahead of print]26(10):

Exploring the Phenotypic Heterogeneity and Bioenergetic Profile of the m.13513G>A mtDNA Substitution: A Heteroplasmy Perspective.

Tatiana Krylova, Yulia Itkis, Polina Tsygankova, Denis Chistol, Konstantin Lyamzaev, Vyacheslav Tabakov, Svetlana Mikhaylova, Natalia Nikitina, Galina Rudenskaya, Aysylu Murtazina, Tatiana Markova, Natalia Semenova, Natalia Buchinskaya, Elena Saifullina, Hasyanya Aksyanova, Peter Sparber, Natalia Andreeva, Natalia Venediktova, Alina Ivanushkina, Daria Eliseeva, Yulia Murakhovskaya, Natalia Sheremet, Ekaterina Zakharova.

  The m.13513G>A (p.Asp393Asn) substitution in the MT-ND5 (Mitochondrially Encoded NADH/Ubiquinone Oxidoreductase Core Subunit 5) gene is a common pathogenic variant associated with primary mitochondrial disorders. It frequently causes Leigh syndrome and mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). In this study, we present clinical data, heteroplasmy levels in various tissues (blood, urine, and skin fibroblasts), and bioenergetic characteristics from a cohort of 20 unrelated patients carrying the m.13513G>A mutation, classified according to the following phenotypes: Leigh syndrome (n = 12), MELAS (n = 2), and Leber's hereditary optic neuropathy (LHON, n = 6). We observed a significant correlation between high respiratory ratios and heteroplasmy levels in fibroblast cell lines of the patients. Furthermore, fibroblast cell lines with heteroplasmy levels exceeding 55% exhibited markedly reduced mitochondrial membrane potential. These findings contribute to a better understanding of the clinical and bioenergetic profiles of patients with m.13513G>A-variant-related phenotypes across different heteroplasmy levels, based on data from a single genetic center. Our data suggest that even a slight shift in heteroplasmy can improve cellular function and, consequently, the patients' phenotype, providing a solid foundation for the development of future gene therapies for mtDNA diseases.

Keywords:  LHON; Leigh; MELAS; heteroplasmy; mtDNA; respirometry

DOI:  https://doi.org/10.3390/ijms26104565
Int J Mol Sci. 2025 May 13. pii: 4668. [Epub ahead of print]26(10):

Cellular Metabolic Disorders in a Cohort of Patients with Sjogren's Disease.

Julian L Ambrus, Alexander Jacob, Abhay A Shukla.

  Metabolism disorders have been seen in multiple autoimmune diseases, including SLE and Sjogren's disease. The current studies were designed to evaluate mutations in genes involved in metabolism in a cohort of patients with Sjogren's disease, diagnosed from clinical criteria and the presence of antibodies to salivary gland antigens. Patients were from an Immunology clinic that follows a large population of patients with autoimmune and metabolic disorders. The patients included in these studies were patients who met the criteria for Sjogren's disease and for whom we were able to obtain genetic studies, sequencing of the mitochondrial DNA, and whole exome sequencing. There were 194 of these patients, and 192 had mutations in one or more gene involved in metabolism: 188 patients had mutations in mitochondrial respiratory chain genes, 17 patients had mutations in mitochondrial tRNA genes, 10 patients had mutations in mitochondrial DLOOP regions, 6 patients had mutations involved in carnitine transport, 6 patients had mutations in genes causing mitochondrial depletion, and 7 patients had glycogen storage diseases. In all cases, the treatment of the metabolic disorder led to symptomatic improvement in energy, exercise tolerance, gastrointestinal dysmotility, and the management of infections. In conclusion, metabolic disorders are common in patients with Sjogren's disease and may be one of the factors leading to the initiation of the disease. The treatment of patients with Sjogren's disease should include the treatment of the underlying/associated metabolic disorder.

Keywords:  Sjogren’s disease; autoantibodies; metabolism

DOI:  https://doi.org/10.3390/ijms26104668
EPMA J. 2025 Jun;16(2): 239-264

Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.

Qianwen Shao, Marie Louise Ndzie Noah, Olga Golubnitschaja, Xianquan Zhan.

  Mitochondria are the primary sites for aerobic respiration and play a vital role in maintaining physiologic function at the cellular and organismal levels. Physiologic mitochondrial homeostasis, functions, health, and any kind of mitochondrial impairments are associated with systemic effects that are linked to the human health and pathologies. Contextually, mitochondria are acting as a natural vital biosensor in humans controlling status of physical and mental health in a holistic manner. So far, no any disorder is known as happening to humans independently from a compromised mitochondrial health as the cause (primary mitochondrial dysfunction) or a target of collateral damage (secondary mitochondrial injury). This certainty makes mitochondrial medicine be the superior instrument to reach highly ambitious objectives of predictive, preventive, and personalized medicine (PPPM/3PM). 3PM effectively implements the paradigm change from the economically ineffective reactive medical services to a predictive approach, targeted prevention and treatments tailored to individualized patient profiles in primary (protection against health-to-disease transition) and secondary (protection against disease progression) healthcare. Mitochondrial DNA (mtDNA) properties differ significantly from those of nuclear DNA (nDNA). For example, mtDNA as the cell-free DNA molecule is much more stable compared to nDNA, which makes mtDNA be an attractive diagnostic target circulating in human body fluids such as blood and tear fluid. Further, genetic variations in mtDNA contribute to substantial individual differences in disease susceptibility and treatment response. To this end, the current gene editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas, are still immature in mtDNA modification, and cannot be effectively applied in clinical practice posing a challenge for mtDNA-based therapies. In contrast, comprehensive multiomics technologies offer new insights into mitochondrial homeostasis, health, and functions, which enables to develop more effective multi-level diagnostics and targeted treatment strategies. This review article highlights health- and disease-relevant mitochondrial particularities and assesses involvement of mitochondrial medicine into implementing the 3PM objectives. By discussing the interrelationship between 3PM and mitochondrial medicine, we aim to provide a foundation for advancing early and predictive diagnostics, cost-effective targeted prevention in primary and secondary care, and exemplify personalized treatments creating proof-of-concept approaches for 3PM-guided clinical applications.

Keywords:  Autophagy and mitophagy; Cancer; Cardio-vascular disease; Chronic Fatigue; Cost-effective tailored treatments; Environment; Health policy; Health-to-disease transition; Individualized patient profile; Metabolic disease; Mitochondrial medicine; Neurodegeneration; Predictive Preventive Personalized Medicine (PPPM / 3PM / 3P medicine); Signaling; Stress; Vital biosensor

DOI:  https://doi.org/10.1007/s13167-025-00409-4
Pediatr Dev Pathol. 2025 May 26. 10935266251335065

Infant With a Severe Form of GLRX5-Related Atypical Hyperglycinemia Exhibiting Novel Cardiac and Neurologic Disease Manifestations at Autopsy.

Elizabeth O Ferreira, Marc R Del Bigio, Jason Morin, Patrick Frosk.

  Glutaredoxin 5 (GLRX5) is a mitochondrial protein encoded by the GLRX5 gene, which is essential for cellular redox homoeostasis, lipoic acid synthesis, and iron-sulfur cluster transfer. Rare cases of pathogenic GLRX5 mutations have been associated with sideroblastic anemia and non-ketotic hyperglycinemia with progressive spasticity and cavitating leukoencephalopathy. We report an 11-month-old child, who died following aspiration, with severe cardiomyocyte mitochondrial abnormalities and cerebral white matter degeneration in the context of a homozygous GLRX5 variant (c.208A>G, p.S70G).

Keywords:  GLRX5 (glutaredoxin-5); cardiomyopathy; metabolic acidosis; mitochondrial disease; non-ketotic hyperglycinemia; progressive spasticity

DOI:  https://doi.org/10.1177/10935266251335065
Am J Ophthalmol Case Rep. 2025 Jun;38 102346

The crossroads of Leber hereditary optic neuropathy and autosomal dominant optic Atrophy: Clinical profiles of patients with coexisting pathogenic genetic variants.

Mohammed A Halawani, Nooran O Badeeb.

   Purpose: Leber Hereditary Optic Neuropathy (LHON) and Autosomal Dominant Optic Atrophy (ADOA) are hereditary optic neuropathies characterized by mitochondrial dysfunctions causing destruction to the retinal ganglion cells and their axons, painless bilateral vision loss and symmetrical temporal pallor of the optic nerve. We present six intrafamilial cases with different manifestations of LHON and/or ADOA and their genetic variant profiles.
Observations: Two brothers and their father had symptomatic bilateral vision loss, two sisters were asymptomatic, and the mother had left eye vision loss due to solar retinopathy; accompanied with headaches. Five of the patients had normal anterior and posterior segment exam aside from the affected optic nerves. The family pedigree showed an unaffected first generation and an affected male in the second generation. In the third generation, an affected male (the father in this family), diagnosed with optic atrophy due to OPA1 c.2383C > T variant, married a woman (the mother) carrying the LHON MT-ND4 m.11778G > A variant. Their offspring were one unaffected daughter, one affected daughter and two affected sons harboring both LHON and ADOA pathogenic variants inherited from their parents.
Conclusion and importance: Mitochondrial optic neuropathies, which result in loss of retinal ganglion cells, are a substantial cause of visual impairment. Herein, we report two cases of combined LHON- and ADOA-causing pathogenic variants in two brothers, in addition to the genetic and ophthalmologic profile of their parents and two sisters.

Keywords:  Autosomal dominant optic atrophy (ADOA); Leber hereditary optic neuropathy (LHON); Pathogenic variants; Vision loss

DOI:  https://doi.org/10.1016/j.ajoc.2025.102346
Cell Tissue Res. 2025 May 26.

Tissue-specific differences impacts therapeutic outcomes of mitochondrial transplantation through regulation of bioenergetics in metabolic syndrome.

Jyotsna Pareek, Pallavi Mudgal, Nitika Sindhu, Vaibhav Tiwari, Dinesh Mani Tripathi, Swati Paliwal.

  Mitochondria transplantation is an emerging therapeutic strategy with remarkable potential in treating various diseases associated with mitochondrial dysfunction. Despite the known differences in tissue-specific mitochondria, the therapeutic outcomes of mitochondria isolated from various sources, after their transplantation in a specific disease model has remained elusive. In this study, we investigated the tissue-dependent therapeutic differences after transplantation of mitochondria isolated from heart, muscle, and liver tissues in a high-fat diet and streptozotocin, 35 mg/Kg (HFD + STZ) induced metabolic syndrome (MetS) in Wistar rats. We found striking differences in lowering of blood glucose levels, blood pressure, cholesterol, ALT, and AST levels in MetS after transplantation of mitochondria obtained from heart, muscle, and liver tissues (P < 0.01). Liver mitochondria transplantation demonstrated the most effective upregulation of mitochondrial complex activities, enhanced anti-oxidant enzyme levels in recipient liver tissues (P < 0.01). It also upregulated gene expression of genes associated with mitochondrial biogenesis and bioenergetics and reduced apoptosis and inflammation associated genes in HFD + STZ rats. In addition, GC-MS metabolite analysis revealed differential blood serum concentrations of key tri-carboxylic acid metabolites such as succinic acid, malic acid, alpha-ketoglutarate, citric acid, and pyruvate after mitochondrial transplantation in HFD + STZ rats. This study supports the idea that mitochondria source tissue should be considered to provide better clinical outcomes for mitochondrial transplantation.

Keywords:  Metabolic syndrome; Mitochondrial transplantation; Therapeutic potential; Tissue source

DOI:  https://doi.org/10.1007/s00441-025-03977-z
Nat Commun. 2025 May 27. 16(1): 4909

Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.

Yao Zhang, Peng Ma, Saifei Wang, Shuxin Chen, Hansong Deng.

Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa2+) levels were elevated while mitochondrial calcium (MitoCa2+) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa2+ was decoupled from the intracellular calcium network and whether the reduction of MitoCa2+ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa2+ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa2+ and Mitochondria-ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa2+ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.

DOI: https://doi.org/10.1038/s41467-025-60196-4
Nat Commun. 2025 May 30. 16(1): 5041

In vivo structure profiling reveals human cytosolic and mitochondrial tRNA structurome and interactome in response to stress.

Noah Peña, Yichen Hou, Christopher P Watkins, Sihao Huang, Wen Zhang, Christopher D Katanski, Tao Pan.

Transfer RNA (tRNA) is the most abundant cellular RNA family in terms of copy numbers. It not only folds into defined structures but also has complex cellular interaction networks involving aminoacyl-tRNA synthetases, translation factors, and ribosomes. The human tRNAome is comprised of chromosomal-encoded tRNAs with a large sequence diversity and mitochondrial-encoded tRNAs with A/U-rich sequences and noncanonical tertiary interactions. How tRNA folding and interactions in a eukaryotic cell respond to stress is poorly understood. Here, we develop DM-DMS-MaPseq, which utilizes in vivo dimethyl-sulfate (DMS) chemical probing and mutational profiling (MaP) coupled with demethylase (DM) treatment in transcriptome-wide tRNA sequencing to profile structures and the cellular interactions of human chromosomal and mitochondrial-encoded tRNAs. We found that tRNAs maintain stable structures in vivo, but the in vivo DMS profiles are vastly different from those in vitro, which can be explained by their interactions with cellular proteins and the ribosome. We also identify cytosolic and mitochondrial tRNA structure and interaction changes upon arsenite treatment, a type of oxidative stress that induces translational reprogramming, which is consistent with global translation repression in both compartments. Our results reveal variations of tRNA structurome and dynamic interactome that have functional consequences in translational regulation.

DOI: https://doi.org/10.1038/s41467-025-59435-5
Redox Biol. 2025 May 20. pii: S2213-2317(25)00205-8. [Epub ahead of print]84 103692

Cannabinol (CBN) alleviates age-related cognitive decline by improving synaptic and mitochondrial health.

Nawab John Dar, Antonio Currais, Taketo Taguchi, Nick Andrews, Pamela Maher.

  Age-related cognitive decline and neurodegenerative diseases, such as Alzheimer's disease, represent major global health challenges, particularly with an aging population. Mitochondrial dysfunction appears to play a central role in the pathophysiology of these conditions by driving redox dysregulation and impairing cellular energy metabolism. Despite extensive research, effective therapeutic options remain limited. Cannabinol (CBN), a cannabinoid previously identified as a potent inhibitor of oxytosis/ferroptosis through mitochondrial modulation, has demonstrated promising neuroprotective effects. In cell culture, CBN targets mitochondria, preserving mitochondrial membrane potential, enhancing antioxidant defenses and regulating bioenergetic processes. However, the in vivo therapeutic potential of CBN, particularly in aging models, has not been thoroughly explored. To address this gap, this study investigated the effects of CBN on age-associated cognitive decline and metabolic dysfunction using the SAMP8 mouse model of accelerated aging. Our results show that CBN significantly improves spatial learning and memory, with more pronounced cognitive benefits observed in female mice. These cognitive improvements are accompanied by sex-specific changes in metabolic parameters, such as enhanced oxygen consumption and energy expenditure. Mechanistically, CBN modulates key regulators of mitochondrial dynamics, including mitofusin 2 (MFN2) and dynamin-related protein 1 (DRP1), while upregulating markers of mitochondrial biogenesis including mitochondrial transcription factor A (TFAM) and translocase of outer mitochondrial membrane 20 (TOM20). Additionally, CBN upregulates key synaptic proteins involved in vesicle trafficking and postsynaptic signaling suggesting that it enhances synaptic function and neurotransmission, further reinforcing its neuroprotective effects. This study provides in vivo evidence supporting CBN's potential to mitigate age-related cognitive and metabolic dysfunction, with notable sex-specific effects, highlighting its promise for neurodegenerative diseases and cognitive decline.

Keywords:  Age-related cognitive decline; Cannabinol (CBN); Mitochondrial biogenesis; Mitochondrial dysfunction; Neuroprotection; SAMP8 mouse model; Sex-specific effects; Synaptic function

DOI:  https://doi.org/10.1016/j.redox.2025.103692
Nat Commun. 2025 May 27. 16(1): 4921

Genetically encoded fluorescent reporter for polyamines.

Pushkal Sharma, Colin Y Kim, Heather R Keys, Shinya Imada, Alex B Joseph, Luke Ferro, Tenzin Kunchok, Rachel Anderson, Yulin Sun, Ömer H Yilmaz, Jing-Ke Weng, Ankur Jain.

Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conduct a genome-wide CRISPR screen and uncover an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for Parkinson's disease. By offering a lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development.

DOI: https://doi.org/10.1038/s41467-025-60147-z
Biochim Biophys Acta Mol Basis Dis. 2025 May 28. pii: S0925-4439(25)00278-9. [Epub ahead of print] 167930

Deficiency in the conserved ECHS1 gene causes Leigh syndrome by impairing mitochondrial respiration efficiency and suppressing ADRB2-PKA signaling.

Baojiang Wang, Yueyuan Qin, Yantao Bao, Shiguo Chen, Junge Zheng, Sheng Lin, Kaifeng Zheng, Shan Duan.

  Deficiency in the short-chain enoyl-CoA hydratase 1 (ECHS1) gene causes Leigh Syndrome (LS), a rare inherited metabolic disorder. Despite LS that arises as a result of inborn errors of energy metabolism, the specific contributions of ECHS1 deficiency to energy metabolism processes, developmental delay, and its mediated signaling mechanism remain unclear. Here, we identify a novel compound heterozygous variant [c.724G > A (p.Glu242Lys) and c.865G > A (Asp289Asn)] in the ECHS1 gene from a family of Han Chinese descent, with the affected individual displaying typical LS symptoms. The ECHS1 variants exhibit reduced 2-enoyl-CoA hydratase activity, resulting in a restricted ATP production rate, but the cellular ATP levels remains unchanged. ECHS1 deficiency also decreases cell viability and proliferation. Mechanistically, ECHS1 interacts with ADRB2, and its variants suppress the ADRB2/protein kinase A (PKA) signaling. Treatment with PKA signaling agonists or overexpression of PKA subunits in ECHS1-deficient cells can rescue the ATP production rate and restore cell viability. Additionally, the mitochondrial E3 ligase MUL1 mediates the ubiquitylation and degradation of ECHS1 protein variants. In conclusion, our study suggests that ECHS1 deficiency impairs mitochondrial respiratory efficiency, thereby lowering the ATP production rate, and reveals a promising therapeutic approach by targeting ADRB2/PKA signaling to combat ECHS1 deficiency-induced LS.

Keywords:  ADRB2; Developmental delay; ECHS1 deficiency; Leigh syndrome; Mitochondrial respiration; Neurodegenerative conditions

DOI:  https://doi.org/10.1016/j.bbadis.2025.167930
Nat Aging. 2025 May 27.

Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.

Zhenguo Wang, Zhe Li, Hongyu Liu, Chenghua Yang, Xin Li.

Mitochondria rapidly accumulate mutations throughout a lifetime, potentially acting as a molecular clock for aging and disease. We profiled mitochondrial RNA across 47 human tissues from 838 individuals, revealing rapid development of clonal mosaicism with two distinct tissue-specific aging signatures. Tissues with constant cellular turnover such as the gastrointestinal tract or skin exhibit accelerated accumulation of sporadic mutations and clonal expansions, implicating increased susceptibility to age-related tumorigenesis and dysfunction. By contrast, post-mitotic tissues, such as the heart and brain, accumulate mutations at deterministic hotspots (tissue-specific, recurrently mutated sites), reflecting the cumulative burden of high energy demand and mitochondrial turnover independent of cell division. These findings support a biphasic model of the mitochondrial clock: stochastic clonal expansion of sporadic replication errors in proliferative tissues, versus age-dependent heteroplasmy increases at hotspots in high-metabolic tissues. This mutational landscape provides a map of tissue-specific vulnerabilities during aging and offers potential therapeutic targets.

DOI: https://doi.org/10.1038/s43587-025-00890-6
Toxicol Res (Camb). 2025 Jun;14(3): tfaf070

PGC-1 alpha regulates mitochondrial biogenesis to promote silica-induced pulmonary fibrosis.

Xiaoqiang Han, Mei Zhang, Liu Daowei, Lulu Liu, Xin Ma, Yu Xiong, Huifang Yang, Zhihong Liu, Na Zhang.

  Silicosis is an incurable chronic fibrotic lung disease caused by long-term exposure to respirable silica particles. It is characterized by persistent inflammation and progressive fibrosis of lung tissues, which eventually leads to respiratory failure and seriously affects human health. The high incidence and mortality associated with silicosis have made the disease a widespread public health concern. However, its pathogenesis has not been fully elucidated. Mitochondrial biogenesis plays a crucial role under various fibrotic conditions. However, the mechanism of this process in silicosis is still unclear. Therefore, this study aimed to explore the influence of the PGC-1α gene on mitochondrial biogenesis in the development of silicosis. We established in vivo and in vitro silicosis models by exposing rats and rat type-2 alveolar epithelial cells (RLE-6TN) to silica. Our findings revealed alterations in the mitochondrial structure and function, decreased mitochondrial biogenesis, and reduced expression of mtDNA (Mitochondrial DNA) content. By upregulating the PGC-1α gene in RLE-6TN cells, we activated the PGC-1α- NRF1-TFAM signaling pathway, enhancing mitochondrial biogenesis, increasing citrate synthase and mtDNA content, improving mitochondrial function, and mitigating fibrosis. Our results indicate that the regulation of mitochondrial biogenesis can affect silicosis-induced fibrosis, highlighting the significance of reduced mitochondrial biogenesis in the progression of silicosis-induced fibrosis.

Keywords:  PGC-1α; mitochondrial biogenesis; pulmonary fibrosis; silica; silicosis

DOI:  https://doi.org/10.1093/toxres/tfaf070
Nature. 2025 May 28.

CoQ imbalance drives reverse electron transport to disrupt liver metabolism.

Renata L S Goncalves, Zeqiu Branden Wang, Jillian K Riveros, Güneş Parlakgül, Karen E Inouye, Grace Yankun Lee, Xiaorong Fu, Jani Saksi, Clement Rosique, Sheng Tony Hui, Mar Coll, Ana Paula Arruda, Shawn C Burgess, Isabel Graupera, Gökhan S Hotamışlıgil.

Mitochondrial reactive oxygen species (mROS) are central to physiology1,2. Excess mROS production has been associated with several disease states2,3; however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH2 to CoQ (CoQH2/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH2/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.

DOI: https://doi.org/10.1038/s41586-025-09072-1
Orphanet J Rare Dis. 2025 May 27. 20(1): 256

mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node.

Laura Mantoan Ritter, Nicholas M P Annear, Emma L Baple, Leila Y Ben-Chaabane, Istvan Bodi, Lauren Brosson, Jill E Cadwgan, Bryn Coslett, Andrew H Crosby, D Mark Davies, Nicola Daykin, Stefanie Dedeurwaerdere, Christina Dühring Fenger, Elaine A Dunlop, Frances V Elmslie, Marie Girodengo, Sophie Hambleton, Anna C Jansen, Simon R Johnson, Kelly C Kearley, John C Kingswood, Liisi Laaniste, Katherine Lachlan, Andrew Latchford, Ralitsa R Madsen, Sahar Mansour, Simeon R Mihaylov, Louwai Muhammed, Claire Oliver, Tom Pepper, Lettie E Rawlins, Ina Schim van der Loeff, Ata Siddiqui, Pooja Takhar, Katrina Tatton-Brown, Andrew R Tee, Priyanka Tibarewal, Charlotte Tye, Sila K Ultanir, Bart Vanhaesebroeck, Benjamin Zare, Deb K Pal, Joseph M Bateman.

  Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.

Keywords:  AKT; Birt-Hogg-Dubé; Everolimus; PI3K; PTEN; Peutz-Jeghers; Rapamycin; Rare diseases; Tuberous sclerosis complex; mTOR

DOI:  https://doi.org/10.1186/s13023-025-03740-1
Cell Death Discov. 2025 May 30. 11(1): 259

Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy.

Shi-Qi Yao, Jia-Jian Liang, Hui Zhou, Shaoying Tan, Yingjie Cao, Chong-Bo Chen, Ciyan Xu, Ruixi Wang, Tai-Ping Li, Fang-Fang Zhao, Yun Wang, Han-Jie He, Dan Zhang, Meng Wang, Lifang Liu, Patrick Yu-Wai-Man, Shihui Wei, Ling-Ping Cen.

Autosomal dominant optic atrophy (ADOA) caused by mutations in the nuclear-encoded OPA1 gene result in the preferential loss of retinal ganglion cells (RGCs) and progressive optic nerve degeneration. The severity of ADOA can be highly variable. This study compared the pathophysiological consequences of the c.1034 G > A OPA1 missense mutation and the c.1305+2delGT OPA1 deletion. There was a significant correlation between the severity of visual loss and the extent of macular RGC loss as determined by optical coherence tomography imaging. In cells transfected with the c.1034 G > A mutant, the percentage of fragmented mitochondria was greater than 60% with cytochrome c (cyt c) overflow, and significantly elevated levels of reactive oxygen species (ROS) and apoptosis. In contrast, the c.1305+2delGT mutant caused mitochondrial fragmentation in ~ 20% of HeLa cells, resulting in less cyt c overflow and apoptosis. The extent of mitochondrial network fragmentation and apoptosis increased with decreasing WT OPA1 mRNA expression levels. The c.1034 G > A OPA1 missense mutation is likely to induce a dominant-negative effect compared with haploinsufficiency with the c.1305+2delGT OPA1 deletion. These contrasting pathophysiological mechanisms could influence disease severity in ADOA through their differential consequences on mitochondrial structure and function. The small drug molecule Paromomycin was able to rescue the mitochondrial fragmentation induced by the c.1034 G > A mutation, providing proof-of-concept for further therapeutic validation in ADOA.

DOI: https://doi.org/10.1038/s41420-025-02442-8
Acta Neurol Belg. 2025 May 28.

MICU1 myopathy revisited: phenotypic variability in a rare mitochondrial calcium disorder.

Pushkar Pazhani, Jayaram Saibaba, Rajeswari Aghoram, Vaibhav Wadwekar, Ankith K Jayan.



Keywords:  Chorea; Extrapyramidal signs; Keloid; Myopathy; Sensory neuropathy

DOI:  https://doi.org/10.1007/s13760-025-02815-x
J Inherit Metab Dis. 2025 Jul;48(4): e70045

A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism.

Aaron Bender, Pablo Ranea-Robles, Evan G Williams, Mina Mirzaian, J Alexander Heimel, Christiaan N Levelt, Ronald J Wanders, Johannes M Aerts, Jun Zhu, Johan Auwerx, Sander M Houten, Carmen A Argmann.

  For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited, in part explaining their unmet medical needs. The expressivity of IEM disease phenotypes is affected by disease-modifying factors, including rare and common polygenic variation. We hypothesize that we can identify these modulating pathways using molecular signatures of IEM in combination with multiomic data and gene regulatory networks generated from non-IEM animal and human populations. We tested this approach by identifying and subsequently validating glucocorticoid signaling as a candidate modifier of mitochondrial fatty acid oxidation disorders, and recapitulating complement signaling as a modifier of inflammation in Gaucher disease. Our work describes a novel approach that can overcome the rare disease-rare data dilemma and reveal new IEM pathophysiology and potential drug targets using multiomics data in seemingly healthy populations.

Keywords:  Bayesian gene regulatory networks; QTL mapping; genetic reference population; metabolomics; mouse models; transcriptomics

DOI:  https://doi.org/10.1002/jimd.70045