bims-musmir 2026-10-11 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–10–11
thirteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Inhibiting Glutaminase Reverses Senescence-Associated Mitochondrial Dysfunction and Skeletal Muscle Decline.
Multicancer analysis reveals mtDNA copy number as a key determinant of mutational load and cancer progression.
Mitochondrial oxidative stress in skeletal muscle alters metabolic signaling responses to acute muscle contraction.
Longer lipids mark aging and constrain lifespan.
Perlecan regulates exercise-induced PGC-1α isoform expression and angiogenic gene program in skeletal muscle.
MicroRNA correlates of resilience to Alzheimer's disease identify candidate therapeutic targets for neuroprotection.
SIRT1 Regulates Late Stage of Autophagy and Mitophagy via Autophagosome-Lysosome Fusion in Cardiomyocytes.
Ketogenic diet induces metabolic remodeling and alters myogenic markers in skeletal muscle of obese male mice subjected to medial meniscus destabilization.
Dissipation of lysosome pH impairs formation and collapses existing LPS-induced lysosome tubules in macrophages.
Cellular Mechanisms Enabling Mitochondria Transfer and Transplantation.
Mitochondrial DNA damage elicits PINK1 upregulation in pontine cholinergic neurons in Parkinson's disease.
The R2TP Complex Couples mTORC1 Signaling to Vacuolar ATPase Assembly and Lysosomal Function.
Inhibition of the Lysosomal Amino Acid Sensor SLC38A9 by the Membrane Microprotein SPAR.

Aging Cell. 2026 Oct;25(10): e70703

Inhibiting Glutaminase Reverses Senescence-Associated Mitochondrial Dysfunction and Skeletal Muscle Decline.

Hamsa Vardini Senthil Kumar, Debanik Choudhury, Pedro Lei, Pihu Mehrotra, Shahryar Shahini, Sydney Swedick, John Toftegaard, Stelios T Andreadis.

Age-associated loss of skeletal muscle mass and function, also known as sarcopenia, is closely linked to mitochondrial dysfunction. In this study, we report that senescent skeletal muscle myoblasts exhibit elevated activity and expression of the enzyme glutaminase (GLS1), which is mediated by p38 MAPK signaling and leads to intracellular urea accumulation that impairs mitochondrial function. Pharmacological inhibition of GLS1 with CB-839 reduced urea levels, restored the expression of electron transport chain (ETC) complexes, and improved mitochondrial function. Consistent with our in vitro findings, CB-839 administration to progeroid mice similarly upregulated ETC complexes and enhanced mitochondrial respiratory capacity in skeletal muscle, leading to improved structural integrity and enhanced muscle strength. Together, these findings suggest that targeting glutamine metabolism via GLS1 inhibition may represent a promising therapeutic strategy to ameliorate age-related skeletal muscle decline by restoring mitochondrial health.

DOI: https://doi.org/10.1111/acel.70703
FEBS J. 2026 Oct 07.

Multicancer analysis reveals mtDNA copy number as a key determinant of mutational load and cancer progression.

Anamika Acharyya, Riddhiman Dhar.

  Mitochondrial DNA (mtDNA) copy number determines the functional state of mitochondria and thus, influences cellular energy production, growth, metabolism, and stress response. Variation in mtDNA copy number has been observed across many cancer types and has been linked to changes in gene expression. However, whether mtDNA copy number has any link to mutation accumulation in cancer is unknown. Further, how mtDNA copy number variation alters expression of cancer-associated pathways and thereby influences cancer progression remains unclear. Here, through an analysis of whole genome data in multiple cancer types, we show that mtDNA copy number increases with an increase in mutational load in cancer samples and the increase in mtDNA copy number bears a signature of compensation for mitochondrial function. We also show that the samples with low-mtDNA generally have increased expression of cancer-promoting genes, including genes involved in cell migration and epithelial-mesenchymal transition (EMT). Taken together, these results reveal a close association of mtDNA copy number with mutational load and disease progression in cancer. These findings provide a way forward toward a better understanding of the role of mtDNA copy number and mitochondrial functional state in cancer progression.

Keywords:  MtDNA copy number; cancer progression; differential expression; epithelial–mesenchymal transition; multicancer analysis; mutational load

DOI:  https://doi.org/10.1111/febs.70736
Free Radic Biol Med. 2026 Oct 07. pii: S0891-5849(26)01182-2. [Epub ahead of print]257 224-240

Mitochondrial oxidative stress in skeletal muscle alters metabolic signaling responses to acute muscle contraction.

Ethan L Ostrom, Aurora Mattson-Hughes, James MacDonald, Theo Bammler, Nicholas J Day, Matthew J Gaffrey, Jesse B Trejo, Wei-Jun Qian, Bo Hagy, Jennifer R Giorgione, Kenneth M Humphries, Holly Van Remmen, Ricard Rodriguez-Mias, Judit Villen, David J Marcinek.

Activation of redox-sensitive signal transduction cascades is an increasingly appreciated mechanism of exercise adaptation in skeletal muscle. Aging and disease are associated with altered redox homeostasis, potentially altering redox responses to muscle contraction, and adaptations to exercise. It is unclear how chronic steady-state changes in redox homeostasis affect contraction-induced signaling cascades. Here we use a novel model of inducible superoxide dismutase 2 knockdown (iSOD2 KD) in skeletal muscle to test how chronic mitochondrial redox perturbations affect subsequent signaling responses to acute fatiguing muscle contraction. After a 12-week doxycycline treatment to knock down SOD2, littermate controls (CON) and iSOD2 KD animals underwent a single acute fatiguing contractile stimulus of the right hindlimb. Muscle tissue was collected immediately after or 3 h after completion of the stimulus followed by redox proteomic and transcriptomic analysis, respectively, and compared to naïve unstimulated controls of each genotype. iSOD2 KD led to decreased protein expression of several key iron-sulfur cluster biosynthesis proteins and increased reversible thiol oxidation of proteins in the mitochondrial compartment in response to muscle contraction. The transcriptomic response to contraction in KD shows activation of apoptosis, oxidative stress, and inflammatory pathways and no significant perturbation in controls. Controls show pathway activation of insulin signaling and glucose metabolism, calcium signaling, and energy stress signaling processes compared to no activation in KD muscle. These results indicate that chronic mitochondrial redox stress shifts acute signaling responses away from metabolic signaling pathways and toward oxidative stress and apoptotic signaling processes which may lead to pathological or maladaptive signaling responses over time.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.10.001
Nat Aging. 2026 Oct 06.

Longer lipids mark aging and constrain lifespan.

Weisha Li, Bauke V Schomakers, Maria M Trętowicz, Laura Hartshorne, Jonathan Sulc, Helgi I Ingólfsson, Tugba N Ozturk, Rob Ofman, Luc Legon, Kasandra Ippel, Michel van Weeghel, Martin A T Vervaart, Eric J M Wever, Simone W Denis, Signe Mosegaard, Adriana S Passadouro, Arwen W Gao, Hans R Waterham, Joris Hoeks, Patrick Schrauwen, Gajja S Salomons, Evan G Wiliams, Paul M L Janssen, Vincent A J Warnaar, Linda Partridge, Johan Auwerx, Sebastian Grönke, Mirre J P Simons, Jolanda van der Velden, Frédéric M Vaz, Riekelt H Houtkooper, Georges E Janssens.

Aging drives molecular changes that impair cellular and tissue function. Lipids are central to membrane structure, signaling and energy storage, yet their remodeling during aging remains unclear. Here, using cross-species, multi-tissue lipidomics, we identify elongation of lipid acyl chains as a conserved hallmark of aging across mice, Caenorhabditis elegans, Drosophila and humans. Similar lengthening occurs during the progression of human heart disease, whereas dietary restriction shortens cardiac lipids in mice. Integrated analyses reveal that aging is characterized by a shift toward longer lipids accompanied by depletion of shorter species, indicating ratiometric remodeling. Following this, we identify the lipid remodeler Plb1 as a regulator of this process, with expression correlating with lifespan in mice and genetic analyses supporting a causal role in human frailty. In C. elegans, Plb1 knockdown reverses lipid elongation and extends lifespan in a lipid-length-dependent manner. Together, these findings establish lipid chain length remodeling as a conserved, actionable hallmark of aging.

DOI: https://doi.org/10.1038/s43587-026-01223-x
Am J Physiol Cell Physiol. 2026 Oct 05.

Perlecan regulates exercise-induced PGC-1α isoform expression and angiogenic gene program in skeletal muscle.

Yuri Yamashita, Kouta Kuwahara, Miyako Nunoya, Sakurako Mihara, Toshinori Yoshihara, Satoshi Nakada, Aurelien Kerever, Manabu Funayama, Eri Arikawa-Hirasawa.

  Exercise induces diverse adaptations in skeletal muscle, and extracellular matrix remodeling plays a key role in these adaptations. Capillaries, which are essential for transporting oxygen and other molecules to maintain skeletal muscle function, are crucial for exercise adaptation. Perlecan, a heparan sulfate proteoglycan and a major basement membrane molecule in skeletal muscle, has been implicated in capillary formation and maintenance. However, its role in exercise adaptation remains unclear. Herein, we used male mice lacking perlecan expression outside of cartilage (Hspg2-/--Tg) as well as Hspg2 wild-type transgenic control mice to examine the regulatory relationship between perlecan and PGC-1α isoforms, which are key mediators of exercise-induced metabolic and angiogenic responses. Following acute treadmill exercise, Hspg2-/--Tg mice showed a significant increase in the mRNA expression of alternative promoter-driven PGC-1α isoforms (ex1b and ex1b') 3 h after exercise, whereas proximal promoter-driven isoforms showed little response. This isoform-specific response was accompanied by enhanced expression of angiogenesis-related genes, including Vegfa, Angpt1, Angpt2, and Hif1a, which peaked 3 h after exercise in perlecan-deficient muscle. In parallel with these transcriptional changes, immunofluorescent analysis revealed significantly higher baseline capillary density in Hspg2-/--Tg quadriceps muscle, a difference that became even more pronounced after 2 wk of exercise training. These findings demonstrate that perlecan deficiency enhances baseline vascular remodeling features and the angiogenic transcriptional response to exercise, suggesting that the composition of the basement membrane extracellular matrix critically regulates exercise-induced PGC-1α isoform expression and muscle-vascular crosstalk during skeletal muscle adaptation.

Keywords:  acute exercise; extracellular matrix; perlecan; skeletal muscle; vascular adaptation

DOI:  https://doi.org/10.1152/ajpcell.00956.2025
bioRxiv. 2026 Aug 10. pii: 2026.08.04.737285. [Epub ahead of print]

MicroRNA correlates of resilience to Alzheimer's disease identify candidate therapeutic targets for neuroprotection.

Pourya Naderi, Latika Matai, Quadri Adewale, Isabel Castanho, Alice Rodrigues, Maria Mavrikaki, Ioannis S Vlachos, Frank J Slack, Winston Hide.

Many aged individuals accumulate advanced Alzheimer's disease (AD) neuropathology without cognitive decline, signifying potent endogenous resilience mechanisms. Mimicking resilience to AD may offer new therapeutic opportunities by emulating endogenous neuroprotection, but the molecular pathways that underpin resilience remain largely unknown. MicroRNAs (miRNAs)-small noncoding RNA molecules that post-transcriptionally regulate gene expression-influence neuronal and glial processes associated with development, aging, and AD neurodegeneration but their role in resilience has not been characterized. We investigated resilience-associated miRNAs and their targeted programs in the dorsolateral prefrontal cortex of post-mortem human brains. We analyzed matched miRNA and messenger RNA (mRNA) expression across resilient, AD, and control subjects from the Religious Order Study and Memory and Aging Project (ROSMAP) cohort. Nine miRNAs were differentially expressed in resilience compared with AD, including previously unreported miR-362-3p and miR-433-3p and new resilience-associated roles for known AD-related miRNAs, including neuronal miR-132-3p and miR-129-5p. By analyzing miRNA activity across AD progression, we found additional cognitive-associated miRNAs (e.g., miR-335-5p and miR-19b) and one plaque-restricted miRNA (miR-199a-5p). Sex-specific miRNA dysregulation was observed: miR-7-5p showed male-specific upregulation in AD versus resilience and suggested sex-specific differences in AD patients. Integrated co-expression and target-enrichment analyses linked resilience-associated miRNAs to pathways that were associated with cognitive decline, including transforming growth factor β, Rho guanosine triphosphatases, and neurotransmitter receptor regulation. We also report restricted co-activity in AD subjects for miR-362-3p with inflammatory pathways, including tumor necrosis factor and Toll-like receptor signaling. These results demonstrate systematic involvement of miRNAs across neuronal and glial programs of AD resilience, cognitive decline, and sex-specific regulation. Our study provides an important resource for discovery of actionable regulatory programs that could lead to new therapies, based on endogenous molecules, that emulate natural resilience to AD.
Key points: Nine distinct cortical microRNA (miRNA) signatures correlate with resilience to Alzheimer's disease (AD)-related cognitive decline, pointing to endogenous regulatory programs that may help preserve cognitive function.At the miRNA level, resilient brains show minimal or no detectable differences to healthy individuals, despite the profound pathological differences, supporting the idea that resilience reflects preserved molecular homeostasis rather than a separate disease state.Some miRNA signatures are specific to a certain pathology (e.g., one linked to amyloid-β plaques independently of tau pathology and cognitive decline), helping to disentangle the regulation of these processes.Sex-specific miRNA dysregulation in AD suggests that resilience-linked pathways may be regulated differently in males and females, reinforcing the value of sex-stratified analyses and the potential for differential therapeutic strategies.Integrative miRNA-pathway analysis highlights candidate regulatory networks involved in inflammation, matrisome, and cellular stress responses, providing a framework for resilience-linked therapeutic targets.

DOI: https://doi.org/10.64898/2026.08.04.737285
FASEB J. 2026 Oct 15. 40(19): e72361

SIRT1 Regulates Late Stage of Autophagy and Mitophagy via Autophagosome-Lysosome Fusion in Cardiomyocytes.

Atsushi Kuno, Yukika Saga, Ryusuke Hosoda, Hiroki Aida, Ayuka Kurihara, Yuki Tatekoshi, Koki Abe, Ryo Numazawa, Naotoshi Iwahara.

  Sirtuin-1 (SIRT1) is an NAD+-dependent deacetylase implicated in autophagosome formation; however, whether SIRT1 also regulates autophagosome clearance during late-stage autophagy remains unclear. Here, we investigated the role of SIRT1 in autophagosome clearance during autophagy and mitophagy in cardiomyocytes. Mitochondrial stress induced by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) decreased mitochondrial protein levels and increased phosphorylation of ubiquitin, a PINK1 target, in H9c2 cardiomyocytes. These CCCP-induced decreases in mitochondrial proteins were prevented by co-treatment with chloroquine, an inhibitor of lysosomal degradation, supporting the induction of CCCP-triggered mitophagy. SIRT1 knockdown similarly prevented the CCCP-induced reduction in mitochondrial proteins and led to the accumulation of autophagosomes containing fragmented mitochondria without attenuating ubiquitin phosphorylation, suggesting that SIRT1 acts downstream of mitochondrial tagging. Tandem GFP-RFP LC3 assay and LC3-LAMP1 colocalization analysis demonstrated impaired autophagosome-lysosome fusion following SIRT1 knockdown. In vivo, cardiomyocyte-specific SIRT1 knockout mice exhibited elevated basal LC3-II levels and a blunted LC3-II response to chloroquine, consistent with impaired autophagic flux. In a doxorubicin (DOX)-treated model, SIRT1 deficiency attenuated autophagosome degradation during the early period after DOX administration. Mechanistically, SIRT1 interacted with Rab7, a key regulator of autophagosome-lysosome fusion, raising the possibility that SIRT1 might regulate fusion through post-translational modification of Rab7 or related components. Collectively, these findings identify SIRT1 as a regulator of autophagosome-lysosome fusion that promotes autophagosome degradation during autophagy and mitophagy in cardiomyocytes.

Keywords:  Sirtuin‐1; autophagosome–lysosome fusion; autophagy; doxorubicin; mitophagy

DOI:  https://doi.org/10.1096/fj.202601047R
J Nutr Biochem. 2026 Oct 09. pii: S0955-2863(26)00257-3. [Epub ahead of print] 110515

Ketogenic diet induces metabolic remodeling and alters myogenic markers in skeletal muscle of obese male mice subjected to medial meniscus destabilization.

Karolina Górecka, Thomas Solé, Kamila Soboska, Karim Chikh, Asmaa El Maarbani, Luciano Pirola, Maura Strigini, Aneta Balcerczyk.

  Osteoarthritis (OA) is strongly associated with obesity, and weight reduction is recommended to reduce joint loading and improve symptoms. However, the effects of ketogenic diet (KD)-induced weight loss on skeletal muscle under combined metabolic and biomechanical stress remain poorly understood. We investigated skeletal muscle adaptation to KD in a mouse model that combined obesity with knee joint injury. Male C57BL/6J mice were rendered obese by high-fat diet feeding and subjected to destabilization of the medial meniscus. Following surgery, animals remained on high-fat diet (HFD) or were switched to chow diet (CD) or KD for 8 weeks. Gastrocnemius muscle was analysed at the molecular level, and serum underwent targeted metabolomic profiling. KD induced weight loss, reduced glycemia and increased circulating β-hydroxybutyrate without decreasing absolute gastrocnemius mass or causing sustained deterioration in motor performance. In skeletal muscle, KD increased Acat1 expression and induced a transcriptional profile consistent with enhanced capacity for lipid-derived substrate utilization, including increased Ppargc1a, Acadl, Cpt1b and Pdk4 expression. These changes were accompanied by selective remodelling of circulating acylcarnitines, particularly long-chain and hydroxyacylcarnitine species, indicating altered systemic. KD also increased expression of the myogenic-associated markers Pax7, Myf5 and MyoD1 hinting at a possible alteration in satellite cell state and pathways connected to myogenesis. Overall, KD promoted selective systemic and skeletal muscle metabolic remodelling in, characterized by altered lipid-derived substrate handling, activation of an oxidative transcriptional program and transcriptional modulation of myogenic-associated markers without sustained deterioration in motor performance during weight loss.

Keywords:  fatty acid oxidation; gastrocnemius muscle; ketogenic diet; ketone bodies; metabolic remodeling; obesity; osteoarthritis; satellite cells; skeletal muscle

DOI:  https://doi.org/10.1016/j.jnutbio.2026.110515
Mol Biol Cell. 2026 Oct 08. mbcE25090457

Dissipation of lysosome pH impairs formation and collapses existing LPS-induced lysosome tubules in macrophages.

Shiraz Anwar, Solmaz Ebrahimi-Iranpour, Maria R Narciso, Jennifer Li, Saaimatul Huq, Tracy Lackraj, Tamara Beriia, Nazia Chowdhury, Mojca Mattiazzi Usaj, Roberto J Botelho.

While lysosomes are typically globular in morphology, lipopolysaccharide-activated macrophages reorganize lysosomes into an expanded tubular network. Here, we sought to determine if the V-ATPase and the lysosomal pH contribute to LPS-mediated lysosome tubulation in macrophages. We found that inhibition of the V-ATPase prevented lysosome tubulation and collapsed preformed tubules. However, the V-ATPase also controls mTORC1 activity, which itself is needed for tubulation. To distinguish between lysosomal pH and mTORC1, we turned to NH4Cl, which alkalinized lysosomal pH but did not interfere with mTORC1; yet NH4Cl blocked tubulation showing that an acidic lysosomal pH is needed for lysosome remodelling. Moreover, clamping the pH to either acidic or alkaline pH caused tubules to collapse, indicating that the pH gradient promotes tubulation, rather than a specific pH. These effects were not due to altered microtubule organization or impaired lysosome motility, suggesting that motors remained associated with lysosomes. On the other hand, while LPS did not alter the average pH of spherical or tubular lysosomes, growing tubules displayed a more acidic peripheral end relative to the pericentral end. Based on this observation, we propose that a localized pH gradient along the tubule may enable tubulation by modulating factors that catalyse tubule growth. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-09-0457
Adv Sci (Weinh). 2026 Oct 06. e78137

Cellular Mechanisms Enabling Mitochondria Transfer and Transplantation.

F Seyma Gokdemir, Yagmur Ozendi, Gokhan Burcin Kubat, Keshav K Singh.

  Mitochondrial transfer and transplantation (mitoTT) has emerged as an experimental and potentially transformative therapeutic strategy, drawing attention for its ability to modulate cellular bioenergetics, stress responses, and tissue repair. Endogenous mitochondrial transfer can occur through tunneling nanotubes, extracellular vesicles, cell fusion, gap junction-associated communication, and phagocytosis-like internalization. These routes differ substantially in distance, directionality, cargo integrity, regulatory control, and physiological relevance. Preclinical studies indicate that exogenous mitochondria may transiently improve bioenergetic function, attenuate oxidative stress, and support recovery in models of cardiac, skeletal muscle, and nervous system injury, whereas clinical evidence remains limited and heterogeneous. Broad clinical implementation remains constrained by unresolved biological and translational barriers. These include inefficient or poorly controlled uptake of extracellular mitochondria, uncertain long-term persistence, incomplete functional integration, donor-recipient incompatibility, mitochondrial-nuclear mismatch, heteroplasmy-related risks, immunogenicity, and the lack of standardized potency and delivery assays. Here, we critically synthesize the cellular mechanisms enabling mitoTT, emphasizing the checkpoints that determine whether transferred mitochondria are integrated, remodeled, immunologically sensed, or eliminated. We further discuss cristae biology and the mitochondrial contact site and cristae organizing system, mitochondrial nucleoid maintenance, mitochondrial DNA replication, organelle contact sites, and emerging bioengineering strategies required to move mitoTT from experimental rescue toward reproducible therapeutic application.

Keywords:  cell metabolism; inter‐organelle contact sites; mitoTT; mitochondria; mitochondrial DNA; mitochondrial transfer; mitochondrial transplantation

DOI:  https://doi.org/10.1002/advs.78137
Brain. 2026 Oct 07. pii: awag348. [Epub ahead of print]

Mitochondrial DNA damage elicits PINK1 upregulation in pontine cholinergic neurons in Parkinson's disease.

Huiwen Lu, Angela Pyle, Jannetta S Steyn, Conor Lawless, Rafiqul Hussain, Maria Falkenberg, Joanna L Elson, Ilse S Pienaar.

  In Parkinson's disease, cholinergic neurons of the pedunculopontine nucleus, located in the upper pons, undergo extensive degeneration, contributing to severe hypokinetic-motor and non-motor symptoms. We previously demonstrated that loss of these neurons is associated with mitochondrial dysfunction, driven by high mitochondrial DNA deletion burden. Increased mitochondrial DNA replication was also observed in these neurons, contrasting with reduced mitochondrial DNA copy number previously reported in Parkinson's-affected surviving nigral-dopaminergic neurons. Here, ultra-deep whole-genome sequencing combined with stringent quality control was used to characterise mitochondrial DNA alterations within single-cell pedunculopontine-cholinergic neurons isolated from Parkinson's-affected and neurologically-normal post-mortem specimens. Analyses included mitochondrial DNA deletion spectrum, -size distribution, genomic location, heteroplasmy levels, breakpoint classification, and point-mutation frequency. Thermodynamic modelling was used to investigate whether the stability of mitochondrial DNA secondary structures surrounding deletion breakpoints could provide insight into the mechanisms underlying mitochondrial DNA deletion formation in Parkinson's disease. In parallel, nuclear-encoded mitochondrial pathway responses were assessed using a customised single-cell multiplexed multi-target gene expression assay, comparing Parkinson's and control post-mortem neurons. Parkinson's-affected neurons exhibited substantial mitochondrial DNA damage, characterised by large-scale mitochondrial DNA deletions predominantly locating within mitochondrial DNA's major arc. Mitochondrial DNA deletions ranged ∼50-5,500 base-pairs, with most exceeding 1,000 base-pairs. Clonal expansion of large-scale mitochondrial DNA deletions, likely arising from replication-associated errors, represented the dominant mutant species. Small mitochondrial DNA deletions (<50bp) were rare, suggesting that free radical-induced strand breakage was not the primary driver of somatic mitochondrial DNA damage. Point-mutation frequency was similar between Parkinson's and control neurons but showed greater functional impact on electron transport chain complex-I subunits in Parkinsonian neurons. Thermodynamic modelling revealed reduced stability of mitochondrial DNA secondary structures flanking mitochondrial DNA deletion breakpoints in Parkinsonian post-mortem neurons, with an average decrease of ∼2 kJ/mol across two major mitochondrial DNA deletions formation models. The increased mitochondrial DNA damage was accompanied by marked upregulation of the nuclear-encoded mitophagy regulator PINK1, specifically in PD patients with extended survival, suggesting activation of a compensatory cytoprotective response. Together, these findings provide comprehensive single-cell resolution profiling of mitochondrial genomic alterations in pedunculopontine-cholinergic neurons in Parkinson's, displaying extensive mitochondrial DNA structural disruption dominated by large-scale mitochondrial DNA deletions. Our results further suggest that upregulation of mitophagy-related pathways may represent an adaptive mechanism to mitigate progressive mitochondrial genomic instability and preserve neuronal energy homeostasis.

Keywords:  Parkinson’s disease; brainstem; cholinergic neurons; mitochondrial DNA; mitophagy; pedunculopontine nucleus

DOI:  https://doi.org/10.1093/brain/awag348
J Cell Biochem. 2026 Oct;127(10): e70133

The R2TP Complex Couples mTORC1 Signaling to Vacuolar ATPase Assembly and Lysosomal Function.

Xiao-Wen Zhang, Ming-Yue Wu, Qi Zhu, Xu Zhuang, Yu Dong, Shuang Zhang, Jia-Hong Lu.

  The vacuolar ATPase (V-ATPase) is essential for lysosomal acidification and autophagy, and its activity is regulated by nutrient-sensitive reversible assembly of its V1 and Vo domains. While mTORC1 is known to inhibit V-ATPase assembly, the precise molecular mechanisms remain incompletely understood. Here, using TurboID-based proximity labeling and quantitative mass spectrometry, we identified the R2TP complex subunits RPAP3 and PIH1D1 as novel autophagy-responsive interactors of the V-ATPase V1A subunit (encoded by ATP6V1A). We found that mTORC1 inhibition disrupts the R2TP-V1A interaction, promoting the relocation of the V1 domain to lysosomes and its assembly with the Vo domain to form active proton pumps. Functionally, knockdown of RPAP3 or PIH1D1 enhanced autophagic flux, increased lysosomal proteolytic activity, and promoted the clearance of soluble α-synuclein in a cellular model of Parkinson's disease (PD). Our study reveals the R2TP complex as a critical molecular switch that couples mTORC1 signaling to V-ATPase assembly and lysosomal function, thereby identifying a new pathway for regulating lysosomal catabolism with significant therapeutic potential for neurodegenerative disorders.

Keywords:  R2TP complex; V‐ATPase; autophagy; lysosomal function; mTORC1

DOI:  https://doi.org/10.1002/jcb.70133
bioRxiv. 2026 Aug 10. pii: 2026.08.07.743590. [Epub ahead of print]

Inhibition of the Lysosomal Amino Acid Sensor SLC38A9 by the Membrane Microprotein SPAR.

Ampon Saeher, Xuelang Mu, Tamir Gonen.

Long noncoding RNAs encode for microproteins that regulate cellular functions. Small regulatory peptide of amino acid response (SPAR) is a microprotein in the lysosome that responds to amino acid availability of the cell. In this study, we investigated the interactions between SPAR and SLC38A9, a lysosomal amino acid transporter and receptor involved in the mechanistic target of rapamycin 1 (mTORC1) pathway. We found that SPAR binds SLC38A9 and inhibits arginine transport in SLC38A9. Moreover, the downstream recruitment of Rag GTPases is also inhibited when SPAR is present in SLC38A9 liposomes. Docking model shows potential interactions between SPAR and SLC38A9. Together, these findings reveal the mechanism of mTORC1 inhibition through microprotein SPAR and illustrates the power of non long coding RNAs in altering cellular functions.
Statement of Significance: Microproteins encoded from long noncoding RNAs are emerging as critical regulators of many pathways. This study investigates a novel mechanism of SPAR microprotein that directly regulates the mechanistic target of rapamycin complex1 (mTORC1) signaling pathway through the lysosomal amino acid transporter SLC38A9. SPAR blocks both arginine transport and the downstream recruitment of Rag GTPases. These findings provide critical results in how SPAR controls cellular amino acid availability, while broadly highlighting the powerful regulatory mechanism of microproteins in cellular processes.

DOI: https://doi.org/10.64898/2026.08.07.743590