bims-polgdi 2025-04-27 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–04–27
25 papers selected by
Luca Bolliger, lxBio

Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.
Mitochondrial DNA signals driving immune responses: Why, How, Where?
Mitochondrial transplantation: Triumphs, challenges, and impacts on nuclear genome remodelling.
Bergenin promotes mitochondrial biogenesis via the AMPK/SIRT1 axis in hepatocytes.
Mechanism of mitochondrial dysfunction on placental trophoblastic cells in intrahepatic cholestasis of pregnancy.
Novel Molecules Targeting Metabolism and Mitochondrial Function in Cardiac Diseases.
ETS2 aggravate allergic airway inflammation by regulating ANT2-mediated cytosolic mitochondrial DsRNA levels.
Exosome-Mediated Mitochondrial Regulation: A Promising Therapeutic Tool for Alzheimer's Disease and Parkinson's Disease.
Origin and evolution of mitochondrial inner membrane composition.
Clinical and Radiological Characterization of TEFM-Associated Neurological Disorder.
Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies.
Therapeutic targeting the cGAS-STING pathway associated with protein and gene: An emerging and promising novel strategy for aging-related neurodegenerative disease.
Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration.
Targeting hypoxia-related pathobiology in Alzheimer's disease: strategies for prevention and treatment.
Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.
rhCC16 Suppresses Cellular Senescence and Ameliorates COPD-Like Symptoms by Activating the AMPK/Sirt1-PGC-1-α-TFAM Pathway to Promote Mitochondrial Function.
Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases.
Induced Pluripotent Stem Cells-Based Regenerative Therapies in Treating Human Aging-Related Functional Decline and Diseases.
Tracing the evolutionary pathway: on the origin of mitochondria and eukaryogenesis.
Cardiac dysfunction due to mitochondrial impairment assessed by human iPS cells caused by DNM1L mutations.
Mitochondrial dysfunction as a key player in aggravating periodontitis among diabetic patients: review of the current scope of knowledge.
Convolutional Neural Network approach to classify mitochondrial morphologies.
Mitochondrial Proteases and Their Roles in Mitophagy in Plants, Animals, and Yeast.
SIRT1-based therapy targets a gene program involved in mitochondrial turnover in a model of retinal neurodegeneration.
Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.

Sci Rep. 2025 Apr 21. 15(1): 13811

Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.

Emi Matsumoto, Taeko Sasaki, Tetsuya Higashiyama, Narie Sasaki.

  Mitochondrial DNA (mtDNA) is organized with proteins into mitochondrial nucleoid (mt-nucleoid). The mt-nucleoid is a unit for the maintenance and function of mtDNA. The regulator of chromosome condensation 1-like protein (RCC1L) performs various functions in mitochondria, including translation, but its involvement in regulating mt-nucleoid maintenance is unknown. Herein, we found that human RCC1L was required to maintain mt-nucleoids and mtDNA. Human RCC1L has three splicing isoforms: RCC1LV1, RCC1LV2, and RCC1LV3. Knockout (KO) cells lacking all RCC1L isoforms, which were lethal without pyruvate and uridine, exhibited a decrease in mt-nucleoids and mtDNA, along with swollen and fragmented mitochondria. Among the three RCC1L isoforms, only RCC1LV1 recovered all phenotypes observed in RCC1L KO cells. As the treatment of wild-type cells with chloramphenicol, a mitochondrial translation inhibitor, did not lead to the decrease in mt-nucleoids accompanied by mtDNA depletion, the decrease in mt-nucleoids and mtDNA in RCC1L KO cells was not solely attributed to impaired mitochondrial translation. Using conditional RCC1L KO cells, we observed a rapid decrease in mt-nucleoids and mtDNA during a specific period following RCC1L loss. Our findings indicate that RCC1L regulates the maintenance of mt-nucleoids and mtDNA besides its role in mitochondrial translational regulation.

Keywords:  Mitochondrial DNA; Mitochondrial nucleoid; RCC1L

DOI:  https://doi.org/10.1038/s41598-025-98397-y
Cell Commun Signal. 2025 Apr 22. 23(1): 192

Mitochondrial DNA signals driving immune responses: Why, How, Where?

Luca Giordano, Sarah A Ware, Claudia J Lagranha, Brett A Kaufman.

  There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.

Keywords:  Circulating cell-free DNA; DNA-sensing receptors; Inflammation; Innate immunity; Mitochondria; Mitochondrial DNA

DOI:  https://doi.org/10.1186/s12964-025-02042-0
Mitochondrion. 2025 Apr 18. pii: S1567-7249(25)00039-X. [Epub ahead of print] 102042

Mitochondrial transplantation: Triumphs, challenges, and impacts on nuclear genome remodelling.

Elly H Shin, Quinn Le, Rachel Barboza, Amanda Morin, Shiva M Singh, Christina A Castellani.

  Mitochondria are membrane-bound organelles of eukaryotic cells that play crucial roles in cell functioning and homeostasis, including ATP generation for cellular energy. Mitochondrial function is associated with several complex diseases and disorders, including cardiovascular, cardiometabolic, neurodegenerative diseases and some cancers. The risk for these diseases and disorders is often associated with mitochondrial dysfunction, particularly the quantitative and qualitative features of the mitochondrial genome. Emerging results implicate mito-nuclear crosstalk as the mechanism by which mtDNA variation affects complex disease outcomes. Experimental approaches are emerging for the targeting of mitochondria as a potential therapeutic for several of these diseases, particularly in the form of mitochondrial transplantation. Current approaches to mitochondrial transplantation generally involve isolating healthy mitochondria from donor cells and introducing them to diseased recipients towards amelioration of mitochondrial dysfunction. Using such a protocol, several reports have shown recovery of mitochondrial function and improved disease outcomes post-mitochondrial transplantation, highlighting its potential as a therapeutic method for several complex, severe and debilitating diseases. Additionally, the mitochondrial genome can be modified prior to transplantation to target disease-associated site-specific mutations and to reduce the ratio of mutant-to-WT alleles. These promising results may underlie the potential impact of mitochondrial transplantation on mito-nuclear genome interactions in the setting of the disease. Further, we recommend that mitochondrial transplantation experimentation include an assessment of potential impacts on remodelling of the nuclear genome, particularly the nuclear epigenome and transcriptome. Herein, we review these and other triumphs and challenges of mitochondrial transplantation as a potential novel therapeutic for mitochondria-associated diseases.

Keywords:  Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial transplantation; Nuclear epigenome; Nuclear transcriptome

DOI:  https://doi.org/10.1016/j.mito.2025.102042
J Med Invest. 2025 ;72(1.2): 66-75

Bergenin promotes mitochondrial biogenesis via the AMPK/SIRT1 axis in hepatocytes.

Yuki Nagara, Kentaro Tsuji, Yuki Kamei, Mitsugu Akagawa.

  Aging and obesity trigger liver mitochondrial decline, impairing liver function and energy metabolism. Effective hepatic mitochondrial biogenesis helps maintain and restore hepatocyte function. The effects of bergenin, a polyphenol with various pharmacological effects, on hepatic mitochondrial biogenesis remain unclear. Therefore, we aimed to determine its effects on mitochondrial biogenesis in hepatocytes. We measured mitochondrial content in human HepG2 hepatocytes using MitoTracker Green FM ; intracellular ATP content using an ATP assay kit ; and mitochondrial DNA (mtDNA) using the ratio of mtDNA to nuclear DNA by qPCR. Protein levels were analyzed using immunoblotting. Nuclear translocation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was assessed by immunofluorescence staining and immunoblotting. In human HepG2 hepatocytes, bergenin increased mitochondrial content, elevated mitochondrial DNA and constituent proteins, and enhanced intracellular ATP levels and PGC-1α nuclear translocation, possibly promoting mitochondrial biosynthesis. SIRT1 expression was induced in bergenin-treated cells and may be responsible for bergenin-inducible mitochondrial biogenesis, which was abolished by the SIRT1 inhibitor EX-527. Furthermore, bergenin activated AMP-activated protein kinase (AMPK). Compound C, an AMPK inhibitor, abolished bergenin-induced SIRT1 expression and mitochondrial biogenesis. Overall, bergenin activates hepatic mitochondrial biogenesis through the AMPK / SIRT1 axis, which could help to prevent and ameliorate serious aging- and obesity-related liver diseases. J. Med. Invest. 72 : 66-75, February, 2025.

Keywords:  bergenin; biogenesis; hepatocytes; mitochondria

DOI:  https://doi.org/10.2152/jmi.72.66
J Mol Histol. 2025 Apr 25. 56(3): 140

Mechanism of mitochondrial dysfunction on placental trophoblastic cells in intrahepatic cholestasis of pregnancy.

Xiaomei Huang, E Liao, Aixing Chen, Yong Shao.

  Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder characterized by elevated serum bile acids and adverse fetal outcomes. Elevated bile acids can lead to excessive accumulation of reactive oxygen species (ROS) in the placenta, and high ROS levels can cause mitochondrial damage. This study primarily investigates the mechanisms of bile acid-induced mitochondrial dysfunction to provide precise targets for the treatment of ICP. Single-cell sequencing of human placental tissues was conducted to analyze changes in mitochondrial function of ICP placental trophoblasts. An ICP cell model was established using TCA, and the effects of TCA on trophoblast mitochondrial function were observed through detection of ROS, mitochondrial membrane potential, fluorescence confocal microscopy, and other methods. Single-cell sequencing indicated significant impairment of mitochondrial function in ICP placental trophoblasts, and electron microscopy results also suggested severe damage to the mitochondrial structure of ICP placental trophoblasts. Both the morphology and function of mitochondria in the ICP cell model were significantly altered, possibly due to impaired mitochondrial transcription mechanisms mediated by NRF1/PGC-1α pathway. Elevated serum bile acids in ICP pregnant women may lead to mitochondrial damage in placental trophoblasts through the NRF1/PGC-1α pathway, thereby affecting the function of placental trophoblasts.

Keywords:  Bile acids; Mitochondria; Placental trophoblasts

DOI:  https://doi.org/10.1007/s10735-025-10427-1
Curr Cardiol Rev. 2025 Apr 18.

Novel Molecules Targeting Metabolism and Mitochondrial Function in Cardiac Diseases.

Samir Bolivar Gonzalez, César Vásquez Trincado, Karen Patricia Torres Rodríguez, Lizeth Paola Forero Acosta, Maria Fernanda Perez García, Steffy Saavedra Castro, Sara Camila Castiblanco Arroyave, Gerardo Manríquez Higuera, Luis Antonio Díaz Ariza, Héctor Rodríguez Ortiz, Evelyn Mendoza-Torres.

  Cardiovascular diseases (CVD) are the leading cause of death worldwide, creating the need for new therapeutic strategies targeting the pathological processes involved. Mitochondria, which comprise one-third of cardiac cell volume, maybe a potential therapeutic target for CVD. Known primarily for energy production, mitochondria are also involved in other processes including intermediary metabolism, mitophagy, calcium homeostasis, and regulation of cell apoptosis. Mitochondrial function is closely linked to morphology, which is altered through mitochondrial dynamics, including processes such as fission and fusion, which ensure that the energy needs of the cell are met. Recent data indicate that mitochondrial dysfunction is involved in the pathophysiology of several CVDs, including cardiac hypertrophy, heart failure, ischemia/reperfusion injury, and cardiac fibrosis. Furthermore, mitochondrial dysfunction is associated with oxidative stress related to atherosclerosis, hypertension, and pulmonary hypertension. In this review, we first briefly present the physiological mechanisms of mitochondrial function in the heart and then summarize the current knowledge on the impact of mitochondrial dysfunction on CVD. And finally, we highlight the evidence from in vitro, in vivo, and clinical studies of the cardioprotective effects of drugs that preserve mitochondrial function in CVD. It is hoped that this review may provide new insights into the need to discover new pharmacological targets with direct actions on mitochondria that may provide combined therapeutic strategies to optimally treat these pathologies.

Keywords:  Cardiovascular disease; angiotensins; cardiac hypertrophy; heart failure; ischemia; metformin; mitochondrial dynamics; nicotinamide riboside.

DOI:  https://doi.org/10.2174/011573403X372565250331190001
Respir Res. 2025 Apr 24. 26(1): 159

ETS2 aggravate allergic airway inflammation by regulating ANT2-mediated cytosolic mitochondrial DsRNA levels.

Hui Jiang, Yaona Jiang, Ran Dong, Chang-Yong Fu.

   BACKGROUND: ETS2 has been identified as a pivotal regulator in the development of human inflammatory diseases. Nevertheless, the functional aspects of ETS2 in asthma remain inadequately characterized. The release of mitochondrial dsRNA is recognized as an initiator of innate immune responses and implicated in intensifying inflammation triggered by alternative immunogens. The interplay between these mechanisms remains poorly understood, and only a limited number of direct targets that underpin the pro-inflammatory role of ETS2 have been identified.
METHODS: The expression of ETS2 in epithelial cells under immune responses was analyzed, and its effects on asthma progression were examined through clinical specimens, human bronchial epithelial cells, and an allergic asthma mouse model. Additionally, the potential involvement of adenine nucleotide translocase-2 in mediating the immune responses regulated by ETS2 was explored.
RESULTS: Increased expression of ETS2 in lung epithelial cells was observed in both asthma patients and ovalbumin (OVA)-induced asthma mice. The deficiency of ETS2 resulted in a substantial decline in inflammatory cell infiltration and markedly diminished IL-6, IL-5, and IL-13 levels in epithelial cells. Mechanistically, ETS2 overexpression was associated with elevated cytosolic mitochondrial RNA levels, whereas knockdown resulted in their suppression. Furthermore, adenine nucleotide translocase-2 (ANT2) expression was robustly upregulated by ETS2 through direct promoter binding. The advantageous effects of ETS2 on asthma development were abrogated in ANT2-deficient mice.
CONCLUSIONS: The findings collectively underscore the role of ETS2 as an exacerbating factor in allergic airway inflammation during asthma progression, primarily by inducing ANT2 expression. Therapeutic targeting of epithelial ETS2 could represent a novel approach to asthma management.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:  ANT2; Asthma; ETS2; Mitochondrial DsRNA; Mitochondrial function

DOI:  https://doi.org/10.1186/s12931-025-03233-6
Int J Nanomedicine. 2025 ;20 4903-4917

Exosome-Mediated Mitochondrial Regulation: A Promising Therapeutic Tool for Alzheimer's Disease and Parkinson's Disease.

Young Hyun Jung, Hyo Youn Jo, Dae Hyun Kim, Yeon Ju Oh, Minsoo Kim, Seunghyun Na, Ho-Yeon Song, Hyun Jik Lee.

  Alzheimer's disease (AD) and Parkinson's disease (PD) are representative neurodegenerative diseases with abnormal energy metabolism and altered distribution and deformation of mitochondria within neurons, particularly in brain regions such as the hippocampus and substantia nigra. Neurons have high energy demands; thus, maintaining a healthy mitochondrial population is important for their biological function. Recently, exosomes have been reported to have mitochondrial regulatory potential and antineurodegenerative properties. This review presents the mitochondrial abnormalities in brain cells associated with AD and PD and the potential of exosomes to treat these diseases. Specifically, it recapitulates research on the molecular mechanisms whereby exosomes regulate mitochondrial biogenesis, fusion/fission dynamics, mitochondrial transport, and mitophagy. Furthermore, this review discusses exosome-triggered signaling pathways that regulate nuclear factor (erythroid-derived 2)-like 2-dependent mitochondrial antioxidation and hypoxia inducible factor 1α-dependent metabolic reprogramming. In summary, this review aims to provide a profound understanding of the regulatory effect of exosomes on mitochondrial function in neurons and to propose exosome-mediated mitochondrial regulation as a promising strategy for AD and PD.

Keywords:  Alzheimer’s disease; Parkinson’s disease; exosome; mitochondria; neurodegenerative disease

DOI:  https://doi.org/10.2147/IJN.S513816
J Cell Sci. 2025 May 01. pii: jcs263780. [Epub ahead of print]138(9):

Origin and evolution of mitochondrial inner membrane composition.

Kailash Venkatraman, Nicolas-Frédéric Lipp, Itay Budin.

  Unique membrane architectures and lipid building blocks underlie the metabolic and non-metabolic functions of mitochondria. During eukaryogenesis, mitochondria likely arose from an alphaproteobacterial symbiont of an Asgard archaea-related host cell. Subsequently, mitochondria evolved inner membrane folds known as cristae alongside a specialized lipid composition supported by metabolic and transport machinery. Advancements in phylogenetic methods and genomic and metagenomic data have suggested potential origins for cristae-shaping protein complexes, such as the mitochondrial contact site and cristae-organizing system (MICOS). MICOS protein homologs function in the formation of cristae-like intracytoplasmic membranes (ICMs) in diverse extant alphaproteobacteria. The machinery responsible for synthesizing key mitochondrial phospholipids - which cooperate with cristae-shaping proteins to establish inner membrane architecture - could have also evolved from a bacterial ancestor, but its origins have been less explored. In this Review, we examine the current understanding of mitochondrial membrane evolution, highlighting distinctions between prokaryotic and eukaryotic mitochondrial-specific proteins and lipids and their differing roles in shaping cristae and ICM architecture, and propose a model explaining the concurrent specialization of the mitochondrial lipidome and inner membrane structure in eukaryogenesis. We discuss how advancements across a range of disciplines are shedding light on how multiple membrane components co-evolved to support the central functions of eukaryotic mitochondria.

Keywords:  Cardiolipin; Cristae; Curvature; Evolution; Mitochondria; Phospholipids

DOI:  https://doi.org/10.1242/jcs.263780
Am J Med Genet A. 2025 Apr 24. e64101

Clinical and Radiological Characterization of TEFM-Associated Neurological Disorder.

Naik Adarsha, Haseena Sait, Deepak Ravichandran.

  Transcription Elongation Factor Mitochondrial (TEFM) is a crucial component of the mitochondrial transcription machinery, playing a key role in regulating mitochondrial RNA (mtRNA) polymerase activity and ensuring efficient mitochondrial DNA transcription. Recent studies have identified pathogenic variations in the TEFM gene as the cause of a childhood-onset neurological disorder with varying severity. To date, only seven cases have been reported in the literature, all from a single study. We report the case of an adolescent male presenting with intellectual disability, behavioral abnormalities, intermittent ataxia, muscle fatigability, lateral rectus ophthalmoplegia, and generalized seizures, along with cerebellar and upper motor neuron signs, as well as unique neuroimaging findings. The intermittent nature of certain symptoms, along with muscle fatigability, resembled a neuromuscular junction (NMJ)-like disorder; however, the repetitive nerve stimulation test (RNST) was normal. Exome sequencing revealed a missense variant (c.469C>G, p.Pro157Ala), which was also observed previously in two Indian siblings. This case expands the phenotypic spectrum of TEFM-related mitochondrial disorders by presenting novel radiological findings not previously described. The identified missense variant may represent a population-specific variant and exhibits a recognizable phenotypic spectrum warranting consideration in individuals presenting with an NMJ-like disorder.

Keywords:  intellectual disability; muscle fatiguability; neuromuscular junction‐like disorder; ophthalmoplegia; transcription elongation factor mitochondrial

DOI:  https://doi.org/10.1002/ajmg.a.64101
EMBO Mol Med. 2025 Apr 22.

Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies.

Sara Clerici, Alessandra Boletta.

  Primary cilia are solitary organelles formed by a microtubule-based skeleton protruding in a single copy on the surface of most cells. Alterations in their function cause a plethora of human conditions collectively called the ciliopathies. The kidney is frequently and severely affected in the ciliopathies, presenting with a spectrum of phenotypes. Cyst formation is a common trait of all renal ciliopathies. Besides this common manifestation, however, the renal ciliopathies present with profoundly different phenotypes, resulting in either polycystic kidney disease (PKD) or nephronophthisis (NPH) phenotypes. The past decade has seen a surge of studies highlighting metabolic reprogramming as a major feature of PKD, with a distinct involvement of mitochondrial dysfunction. This discovery has brought forward the development of novel therapeutic approaches. More recent evidence suggests that primary cilia modulate the mitochondrial production of energy in response to environmental cues. Here, we summarize the evidence available to date and propose a more general involvement of metabolic and mitochondrial alterations in the renal ciliopathies that might in principle help defining the profoundly different, and potentially opposite, manifestations observed.

Keywords:  Cilia; Ciliopathies; Kidney Cysts; Metabolism; Mitochondria

DOI:  https://doi.org/10.1038/s44321-025-00239-x
Int Immunopharmacol. 2025 Apr 18. pii: S1567-5769(25)00669-1. [Epub ahead of print]156 114679

Therapeutic targeting the cGAS-STING pathway associated with protein and gene: An emerging and promising novel strategy for aging-related neurodegenerative disease.

Qiongli Zhou, Jinghao Luo, Xueting Chai, Jirui Yang, Shiyin Zhong, Zhimin Zhang, Xuhong Chang, Hui Wang.

  Neurodegenerative diseases (NDDs) represent a rapidly escalating global health challenge, contributing significantly to the worldwide disease burden and posing substantial threats to public health systems across nations. Among the many risk factors for neurodegeneration, aging is the major risk factor. In the context of aging, multiple factors lead to the release of endogenous DNA (especially mitochondrial DNA, mtDNA), which is an important trigger for the activation of the cGAS-STING innate immune pathway. Recent studies have identified an increasing role for activation of the cGAS-STING signaling pathway as a driver of senescence-associated secretory phenotypes (SASPs) in aging and NDDs. The cGAS-STING pathway mediates the immune sensing of DNA and is a key driver of chronic inflammation and functional decline during the aging process. Blocking cGAS-STING signaling may reduce the inflammatory response by preventing mtDNA release and enhancing mitophagy. Targeted inhibition of the cGAS-STING pathway by biological macromolecules such as natural products shows promise in therapeutic strategies for age-related NDDs. This review aims to systematically and comprehensively introduces the role of the cGAS-STING pathway in age-related NDDs in the context of aging while revealing the molecular mechanisms of the cGAS-STING pathway and its downstream signaling pathways and to develop more targeted and effective therapeutic strategies for NDDs.

Keywords:  Age-related neuroinflammation; Inhibitors; Neurodegenerative diseases; Senescence-associated phenotypes; cGAS–STING pathway

DOI:  https://doi.org/10.1016/j.intimp.2025.114679
Cell Mol Neurobiol. 2025 Apr 21. 45(1): 38

Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration.

Donghui Na, Zechen Zhang, Meng Meng, Meiyu Li, Junyan Gao, Jiming Kong, Guohui Zhang, Ying Guo.

  Aging is characterized by a gradual decline in physiological functions, with brain aging being a major risk factor for numerous neurodegenerative diseases. Given the brain's high energy demands, maintaining an adequate ATP supply is crucial for its proper function. However, with advancing age, mitochondria dysfunction and a deteriorating energy metabolism lead to reduced overall energy production and impaired mitochondrial quality control (MQC). As a result, promoting healthy aging has become a key focus in contemporary research. This review examines the relationship between energy metabolism and brain aging, highlighting the connection between MQC and energy metabolism, and proposes strategies to delay brain aging by targeting energy metabolism.

Keywords:  Brain aging; Energy metabolism; Mitochondrial quality control; Neurons

DOI:  https://doi.org/10.1007/s10571-025-01555-z
Mol Biol Rep. 2025 Apr 23. 52(1): 416

Targeting hypoxia-related pathobiology in Alzheimer's disease: strategies for prevention and treatment.

Veerta Sharma, Reet Verma, Thakur Gurjeet Singh.

   INTRODUCTION: Alzheimer's Disease (AD) is a neurodegenerative condition characterised by cognitive decline and memory impairment. Recent research highlights the important role of hypoxia, a state of insufficient oxygen availability, in exacerbating AD pathogenesis.
MATERIALS AND METHODS: Through the use of a number of different search engines like Scopus, PubMed, Bentham, and Elsevier databases, a literature review was carried out for investigating the role of hypoxia mediated pathobiology in AD. Only peerreviewed articles published in reputable journals in English language were included. Conversely, non-peer-reviewed articles, conference abstracts, and editorials were excluded, along with studies lacking experimental or clinical relevance or those unavailable in full text.
CONCLUSION: Hypoxia exacerbates core pathological features such as oxidative stress, neuroinflammation, mitochondrial dysfunction, amyloid-beta (Aβ) dysregulation, and hyperphosphorylation of tau protein. These interlinked mechanisms establish a self-perpetuating cycle of neuronal damage, accelerating disease progression. Addressing hypoxia as a modifiable risk factor offers potential for both prevention and treatment of AD. Exploring hypoxia and the HIF signalling pathway may help counteract the neuropathological and symptomatic effects of neurodegeneration.

Keywords:  Alzheimer’s disease; HIF-1; Hypoxia; Mitochondrial dysfunction; Neuroinflammation; Oxidative stress

DOI:  https://doi.org/10.1007/s11033-025-10520-4
PLoS Genet. 2025 Apr 25. 21(4): e1011678

Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.

Xiaomeng Yang, Ruichen Wei, Fanfan Meng, Dianchen Liu, Xuan Gong, Gary Ruvkun, Wei Wei.

Mitochondrial fission and fusion are tightly regulated to specify mitochondrial abundance, localization, and arrangement during cell division as well as in the diverse differentiated cell types and physiological states. However, the regulatory pathways for such mitochondrial dynamics are less explored than the mitochondrial fission and fusion components. Here we report a large-scale screen for genes that regulate mitochondrial fission. Mitochondrial fission defects cause a characteristic uneven fluorescent pattern in embryos carrying mitochondrial stress reporter genes. Using this uneven activation, we performed RNAi screens that identified 3 kinase genes from a ~ 500-kinase library and another 11 genes from 3,300 random genes that function in mitochondrial fission. Many of these identified genes play roles in chromosome segregation. We found that chromosome missegregation and genome instability lead to dysregulation of mitochondrial fission, possibly independent of DRP-1. ATL-1, the C. elegans ATR orthologue, plays a potentially protective role in alleviating the mitochondrial fission defect caused by chromosome missegregation. This establishes a screening paradigm for identifying mitochondrial fission regulators, which reveals the potential role of ATR in surveilling mitochondrial fission to mitigate dysregulation caused by improper chromosome segregation.

DOI: https://doi.org/10.1371/journal.pgen.1011678
J Cell Mol Med. 2025 Apr;29(8): e70566

rhCC16 Suppresses Cellular Senescence and Ameliorates COPD-Like Symptoms by Activating the AMPK/Sirt1-PGC-1-α-TFAM Pathway to Promote Mitochondrial Function.

Ying-Jie Ren, Tian-Qi Sun, Yu Lu, Dan-Li Liu, Rui Gao, Ting Li, Min Guo, Qing-Hua Liu, Hai-Long Wang, Min Pang.

  Chronic obstructive pulmonary disease (COPD) is a widespread lung disease marked by alveolar wall damage, leading to inflammation and fibrosis. Key risk factors include age, smoking, sex, and education, with smoking being the most crucial. These factors are globally consistent and linked with aging. Club cell secretory protein 16 (CC16), primarily secreted by non-ciliated bronchial epithelial cells, is crucial for pulmonary health, offering anti-inflammatory and antioxidant benefits. CC16 levels are notably reduced in COPD, suggesting its enhancement as a potential treatment. In this study, cellular senescence of BEAS-2B cells was stimulated using cigarette smoke extract (CSE) and the function of recombinant human CC16 protein (rhCC16) in cellular senescence was assessed by detecting the levels of β-galactosidase, p16, p21, ROS and the underlined mechanism was revealed by measuring mitochondrial biogenesis and metabolism. Additionally, COPD mice were prepared, and rhCC16's role on the cellular senescence of lung tissues was examined. Our findings showed that rhCC16 ameliorated cellular senescence in BEAS-2B cells and lung tissues of COPD mice accompanied by lower levels of β-galactosidase, p16, p21 and ROS. Mechanically, rhCC16 mitigated senescence via triggering PGC-1α expression through the AMPK/SIRT1 pathway and fostering mitochondrial biogenesis and metabolism to reduce the levels of ROS. Furthermore, the results also indicated that rhCC16 exerted its effect via both integrin α4β1 and clathrin-mediated endocytosis. Collectively, rhCC16 suppresses cellular senescence and ameliorates COPD-like symptoms by activating the AMPK/Sirt1-PGC-1-α-TFAM pathway to foster mitochondrial function.

Keywords:  AMPK; COPD; cellular senescence; mitochondrial function; rhCC16

DOI:  https://doi.org/10.1111/jcmm.70566
Mitochondrion. 2025 Apr 17. pii: S1567-7249(25)00037-6. [Epub ahead of print]84 102040

Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases.

Isabel Amador-Martínez, Ana Karina Aranda-Rivera, Mauricio Raziel Martínez-Castañeda, José Pedraza-Chaverri.

  Mitochondria are essential organelles for cellular function and have become a broad field of study. In cardio-renal diseases, it has been established that mitochondrial dysfunction is a primary mechanism leading to these pathologies. Under stress, mitochondria can develop stress response mechanisms to maintain mitochondrial quality control (MQC) and functions. In contrast, the perturbation of these mechanisms has been associated with the pathogenesis of several diseases. Thus, targeting specific pathways within MQC could offer a therapeutic avenue for protecting mitochondrial integrity. However, the mechanisms related to MQC and mitochondrial stress signaling in the cardio-renal axis have been poorly explored. The primary limitations include the lack of reproducibility in the experimental models of cardio-renal disease, the incomplete knowledge of molecules that generate bidirectional damage, and the temporality of the study models. Therefore, we believe that integration of all of those limitations, along with recent advances in MQC mechanisms (i.e., mitophagy), stress signaling pathways (e.g., integrated stress response, mitochondrial unfolded protein response, and mitochondrial protein import), associated pharmacology, and targeted therapeutic approaches could reveal what the deregulation of these mechanisms is like and provide ideas for generating strategies that seek to avoid the progression of cardio-renal diseases.

Keywords:  Cardio-renal disease; Integrated stress response; Mitochondrial dysfunction; Mitochondrial import; Mitochondrial quality control; Mitochondrial unfolded protein response

DOI:  https://doi.org/10.1016/j.mito.2025.102040
Cells. 2025 Apr 21. pii: 619. [Epub ahead of print]14(8):

Induced Pluripotent Stem Cells-Based Regenerative Therapies in Treating Human Aging-Related Functional Decline and Diseases.

Peijie Yu, Bin Liu, Cheng Dong, Yun Chang.

  A significant increase in life expectancy worldwide has resulted in a growing aging population, accompanied by a rise in aging-related diseases that pose substantial societal, economic, and medical challenges. This trend has prompted extensive efforts within many scientific and medical communities to develop and enhance therapies aimed at delaying aging processes, mitigating aging-related functional decline, and addressing aging-associated diseases to extend health span. Research in aging biology has focused on unraveling various biochemical and genetic pathways contributing to aging-related changes, including genomic instability, telomere shortening, and cellular senescence. The advent of induced pluripotent stem cells (iPSCs), derived through reprogramming human somatic cells, has revolutionized disease modeling and understanding in humans by addressing the limitations of conventional animal models and primary human cells. iPSCs offer significant advantages over other pluripotent stem cells, such as embryonic stem cells, as they can be obtained without the need for embryo destruction and are not restricted by the availability of healthy donors or patients. These attributes position iPSC technology as a promising avenue for modeling and deciphering mechanisms that underlie aging and associated diseases, as well as for studying drug effects. Moreover, iPSCs exhibit remarkable versatility in differentiating into diverse cell types, making them a promising tool for personalized regenerative therapies aimed at replacing aged or damaged cells with healthy, functional equivalents. This review explores the breadth of research in iPSC-based regenerative therapies and their potential applications in addressing a spectrum of aging-related conditions.

Keywords:  aging-related diseases; cellular reprogramming; induced pluripotent stem cells; personalized therapies; regenerative medicine

DOI:  https://doi.org/10.3390/cells14080619
FEBS J. 2025 Apr 24.

Tracing the evolutionary pathway: on the origin of mitochondria and eukaryogenesis.

J Ernesto Bravo-Arévalo.

  The mito-early hypothesis posits that mitochondrial integration was a key driver in the evolution of defining eukaryotic characteristics (DECs). Building on previous work that identified endosymbiotic selective pressures as central to eukaryotic cell evolution, this study examines how endosymbiotic gene transfer (EGT) and the resulting genomic and bioenergetic constraints shaped mitochondrial protein import systems. These systems were crucial for maintaining cellular function in early eukaryotes and facilitated their subsequent diversification. A primary focus is the co-evolution of mitochondrial import mechanisms and eukaryotic endomembrane complexity. Specifically, I investigate how the necessity for nuclear-encoded mitochondrial protein import drove the adaptation of bacterial secretion components, alongside eukaryotic innovations, to refine translocation pathways. Beyond enabling bioenergetic expansion, mitochondrial endosymbiosis played a fundamental role in the emergence of compartmentalisation and cellular complexity in LECA, driving the evolution of organellar networks. By integrating genomic, structural and phylogenetic evidence, this study aimed to contribute to the mito-early framework, clarifying the mechanisms that linked mitochondrial acquisition to the origin of eukaryotic cells.

Keywords:  EGT; antimicrobial peptides (AMPs); endosymbiosis; eukaryogenesis; mitochondria; mitochondrial protein import

DOI:  https://doi.org/10.1111/febs.70109
Pediatr Res. 2025 Apr 23.

Cardiac dysfunction due to mitochondrial impairment assessed by human iPS cells caused by DNM1L mutations.

Madori T Osawa, Yasunori Fujita, Kazuki Kagami, Masataka Ito, Yoshiteru Tamura, Shoichiro Tateishi, Junya Take, Fumi Hirose, Hidetoshi Hagiwara, Kohsuke Imai, Daisuke Yoshinaga, Shiro Baba, Mitsujiro Osawa, Hiroko Harashima, Kei Murayama, Yuko Akioka, Akira Ohtake, Ikuro Suzuki, Takeshi Adachi, Takeru Yamazaki, Satoshi Arai, Shiro Matsumoto, Tetsuya Kitaguchi, Megumu K Saito, Ikuroh Ohsawa, Shigeaki Nonoyama.

BACKGROUND: DNM1L encodes dynamin-related protein 1, which plays an important role in mitochondrial and peroxisomal division. The DNM1L mutation leads to cardiac dysfunction in patients and animal models. However, the mechanism of cardiac dysfunction caused by DNM1L mutation has not been elucidated clearly at least in the studies of human cardiomyocytes.
METHODS: We established human induced pluripotent stem cells (hiPSCs) from two pediatric patients with DNM1L mutation. The hiPSCs were differentiated into hiPSC-derived cardiomyocytes (hiPS-CMs). Mitochondrial morphology and function, cardiomyocyte Ca2+ dynamics, and contractile and diastolic function of hiPS-CMs were analyzed.
RESULTS: The morphology of the mitochondria was abnormally elongated in patient-derived hiPS-CMs. The mitochondrial membrane potential and oxygen consumption rate were significantly decreased, resulting in reduced ATP production. In the analysis of Ca2+ dynamics, the 50% time to decay was significantly longer in patient-derived hiPS-CMs than in healthy control. High-precision live-imaging system analysis revealed that contractile and diastolic function was significantly impaired under isoproterenol stimulation.
CONCLUSION: DNM1L mutations cause mitochondrial impairment with less production of ATP in cardiomyocytes. This leads to abnormal intracellular Ca2+ dynamics, resulting in contractile and diastolic dysfunction.
IMPACT: DNM1L mutations was identified in two pediatric patients who developed cardiac dysfunction and human induced pluripotent stem cells (hiPSCs) were established from these two patients and differentiated into hiPSC-derived cardiomyocytes (hiPS-CMs). DNM1L mutations induced abnormal mitochondrial morphology, mitochondrial dysfunction, and insufficient ATP production in hiPS-CMs. In addition, hiPS-CMs with DNM1L mutation showed abnormal Ca2+ kinetics and impaired contractile and diastolic function. This is the first study that elucidate the mechanism of cardiac dysfunction caused by DNM1L mutations by using hiPSCs.

DOI: https://doi.org/10.1038/s41390-025-04045-6
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr 24.

Mitochondrial dysfunction as a key player in aggravating periodontitis among diabetic patients: review of the current scope of knowledge.

Al-Hassan Soliman Wadan, Ahmed Sherief Moshref, Abdullah Mohammed Emam, Youssef Gamal Bakry, Bushra Osama Khalil, Akhilanand Chaurasia, Reham A H Ibrahim, Tamer Badawy, Samah S Mehanny.

  Periodontitis is a prevalent inflammatory disease that leads to significant periodontal tissue destruction and compromised dental health, with its severity exacerbated in individuals with Diabetes Mellitus (DM). This review explores the complex relationship between mitochondrial dysfunction and periodontitis in diabetic patients. Recent studies indicate that the excessive production of reactive oxygen species (ROS), primarily generated by dysfunctional mitochondrial electron transport chain (ETC) complexes, contributes to oxidative stress (OS) and subsequent periodontal tissue damage. The interplay between impaired mitochondrial biogenesis, apoptosis of periodontal cells, and ROS accumulation highlights a critical area of concern in understanding the pathophysiology of diabetic periodontitis. Furthermore, altered glycemic control due to inflammatory processes associated with periodontitis may perpetuate a cyclical detriment to oral and systemic health. This review aims to highlight the mechanistic roles of mitochondrial dysfunction in the aggravation of periodontitis among diabetic patients, emphasizing further research to identify potential therapeutic targets and improve treatment efficacy for this dual pathology.

Keywords:  Cytokines; Diabetes; Mitochondrial dysfunction; Periodontitis; Reactive Oxygen Species (ROS)

DOI:  https://doi.org/10.1007/s00210-025-04025-x
Comput Biol Chem. 2025 Apr 17. pii: S1476-9271(25)00137-9. [Epub ahead of print]118 108477

Convolutional Neural Network approach to classify mitochondrial morphologies.

Soumaya Zaghbani, Lukas Faber, Ana J Garcia-Saez.

  The morphology of the mitochondrial network is a major indicator of cellular health and function, with changes often linked to various physiological and pathological conditions. As a result, efficient methods to quickly assess mitochondrial shape in cellular populations from microscopy images in a quantitative manner are of high interest for the health and life sciences. Here, we present MitoClass, a deep learning-based software designed for automated mitochondrial classification. MitoClass employs a classification algorithm that categorizes mitochondrial network shapes into three classes: fragmented, intermediate, and elongated. By leveraging super-resolution images, we curated a comprehensive dataset for training, including both high- and low-resolution representations of mitochondrial networks. Using a Convolutional Neural Network (CNN) architecture, our model effectively distinguishes between different mitochondrial morphologies. Through rigorous training and validation, MitoClass provides a fast, accurate, and user-friendly solution for researchers and clinicians to assess the organization of the mitochondrial network as a proxy for studying organelle health and dynamics.

Keywords:  Cellular imagin; Convolutional neural network; Deep learning; Image classification; Mitochondria classification; Mitochondria dynamics

DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108477
Plant Cell Physiol. 2025 Apr 23. pii: pcaf038. [Epub ahead of print]

Mitochondrial Proteases and Their Roles in Mitophagy in Plants, Animals, and Yeast.

Kacper Ludwig, Małgorzata Heidorn-Czarna.

  Mitochondria play a central role in cellular respiration and other essential metabolic and signaling pathways. To function properly, mitochondria require the maintenance of proteostasis-a balance between protein synthesis and degradation. This balance is achieved through the mitochondrial protein quality control (mtPQC) system, which includes mitochondrial proteases and mitophagy. Mitochondrial proteases ensure proper protein sorting within the mitochondria and maintain proteome homeostasis by degrading unassembled, damaged, or short-lived regulatory proteins. Numerous studies have demonstrated the critical role of mitochondrial proteases in regulating mitophagy-the selective degradation of damaged, aging, or excess mitochondria or their fragments via autophagy. Notably, the rhomboid PARL protease is involved in ubiquitin-dependent PINK1-Parkin mitophagy in mammals while the i-AAA protease Yme1 plays a role in mitophagy in budding yeast. Despite the conservation of core autophagy genes, knowledge about the molecular mechanisms and protein regulators of mitophagy in plants remains limited. In this review, we discuss recent advances in understanding the roles of mitochondrial proteases and mitophagy across plants, animals, and yeast. By comparing these mechanisms across kingdoms, we highlight the potential regulatory function of the plant i-AAA mitochondrial protease in controlling mitophagy, providing new insights into mitochondrial protein quality control networks in plants.

Keywords:   Arabidopsis thaliana ; i-AAA protease; mitochondria; mitochondrial proteases; mitochondrial protein quality control system; mitophagy

DOI:  https://doi.org/10.1093/pcp/pcaf038
Sci Rep. 2025 Apr 19. 15(1): 13585

SIRT1-based therapy targets a gene program involved in mitochondrial turnover in a model of retinal neurodegeneration.

Brahim Chaqour, Jacob B Rossman, Miranda Meng, Kimberly E Dine, Ahmara G Ross, Kenneth S Shindler.

  Neurodegenerative diseases of the eye such as optic neuritis (ON) are hallmarked by retinal ganglion cell (RGC) loss and optic nerve degeneration leading to irreversible blindness. Therapeutic interventions enhancing expression or activity of SIRT1, an NAD+-dependent deacetylase, support, at least in part, survival of RGCs in the face of injury. Herein, we used mice with experimental autoimmune encephalomyelitis (EAE) which recapitulates axonal and neuronal damages characteristic of ON to identify gene regulatory networks affected by constitutive ubiquitous Sirt1 expression in SIRT1 knock-in mice and wild-type mice upon targeted adeno-associated virus (AAV)-mediated SIRT1 expression in RGCs. RNA seq data analysis showed that the most upregulated genes in EAE mouse retinas include those involved in inflammation, immune response, apoptosis, and mitochondrial turnover. The latter includes genes regulating mitophagy (e.g., Atg4), mitochondrial transport (e.g., Ipo- 6, Xpo- 6), and mitochondrial localization (e.g., Chrna4, Scn9a). The constitutive or RGC-targeted SIRT1 overexpression in EAE mice upregulated the expression of non-mitochondrial genes such as Ecel1 and downregulated the expression of mitophagy genes (e.g., Atg2b, Arifip1) which were upregulated by EAE alone. Thus, SIRT1 induces neuroprotection by, at least in part, balancing mitochondrial biogenesis and mitophagy and/or enhancing mitochondrial self-repair to preserve the bioenergetic capacity of RGCs.

Keywords:  Experimental autoimmune encephalomyelitis; Optic neuritis; SIRT1

DOI:  https://doi.org/10.1038/s41598-025-97456-8
Curr Biol. 2025 Apr 21. pii: S0960-9822(25)00296-9. [Epub ahead of print]35(8): R287-R290

Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.

Mohamed A Eldeeb, Michael Shahid, Edward A Fon.

Dysregulation of mitochondrial protein import induces significant cellular stress. Yet, our understanding of the dialogue between mitochondrial import, the stress it can trigger, and counteracting mechanisms remains incomplete. A recent study unveils how the mitochondrial protease YME1L1 degrades unoccupied mitochondrial translocases during mitochondrial import stress.

DOI: https://doi.org/10.1016/j.cub.2025.03.011