bims-musmir 2026-05-03 papers

EMBO Rep. 2026 Apr 27.

Mitochondrial protein import stress causes lysosomal damage and progressive tissue atrophy.

Nicholas A Brennan, Xiaowen Wang, Arnav Rana, Sanaea Z Bhagwagar, Jason Horton, Patricia M Kane, Xin Jie Chen.

Mitochondrial and lysosomal abnormalities co-occur in aging-related diseases with progressive tissue atrophy. It remains unclear whether these two pathogenic pathways affect tissue homeostasis independently, convergently or epistatically. We show that mitochondrial protein import stress causes vacuolar damage in yeast, manifested by V-ATPase disassembly, and vacuolar deacidification and fragmentation. In a mouse model of mitochondrial protein import stress induced by overloading of the nuclear-encoded ANT1 protein, we observe progressive muscle atrophy independent of bioenergetic defects. Like in yeast mutants with severe vacuolar damage, genes involved in amino acid uptake/biosynthesis, one-carbon metabolism, lysosomal biogenesis and iron homeostasis are activated in the skeletal muscle of Ant1-transgenic mice. The affected muscles accumulate glycogen, lipofuscin and poorly processed multivesicular bodies. Despite activation of lysosomal repair and lysophagic pathways, autophagic flux is severely stalled. During aging, various proteolytic cathepsins are increasingly released from the lysosomal lumen into the cytosol. Together with proteasomal activation, this may contribute to unbalanced proteostasis, reduced myofiber size and skeletal muscle atrophy. Our study therefore discovered an evolutionarily conserved mitochondria-to-lysosome proteotoxic axis that affects tissue mass homeostasis during aging.

DOI: https://doi.org/10.1038/s44319-026-00774-9

Am J Physiol Endocrinol Metab. 2026 Apr 29.

Muscle glycogen metabolism is rapidly dysregulated in critical illness, which may have implications for muscle ATP resynthesis and ICU acquired weakness.

Tom S O Jameson, Benjamin T Wall, Tomáš Urban, Adéla Krajčová, Bob Bakalář, Michal Fric, Kateřina Jiroutková, Valér Džupa, Jan Gojda, Craig Porter, Barbora Miznerová, František Duška, Francis B Stephens.

The association of perturbed skeletal muscle metabolism with ICU acquired weakness (ICUAW) is not clear. The objective of the present study was to characterise temporal changes in skeletal muscle mitochondrial function, ATP concentration, and substrate utilisation during and up to 6 months post ICU admission in critically ill patients, and to delineate mechanisms underpinning ICUAW by comparing the expression of genes involved in skeletal muscle mitochondrial function and substrate utilisation in the critically ill patients to control groups that had either undergone elective surgery or leg immobilisation (i.e. muscle disuse). The study design was a randomised controlled trial of functional electrical stimulation-assisted cycle ergometry (FESCE) vs. standard care, with skeletal muscle mitochondrial respirometry defined a priori in a nested sub-group of patients as the primary outcome. Mitochondrial respirometry did not change 7 days or 6 months after ICU admission and was not impacted by FESCE. However, a 20% reduction in muscle ATP content by day 7 of ICU stay persisted after 6 months and tended to associate with ICUAW (P=0.078, R2=0.582). Moreover, a 40% lower muscle glycogen and 2.5-fold greater muscle lactate were observed earlier at day 1 compared to elective surgery patients. These changes reflected expression of genes related to glycogen metabolism when disuse was accounted for, and of which a greater expression of the gene encoding glycogen phosphorylase (PYGM) was predictive of mortality. We conclude that muscle glycogen metabolism is rapidly dysregulated in critical illness, which may have implications for muscle ATP resynthesis and ICUAW.

Keywords: Functional electrical stimulation; Glycogen metabolism; ICU acquired weakness; Mitochondrial respirometry; Skeletal muscle

DOI: https://doi.org/10.1152/ajpendo.00022.2026

medRxiv. 2026 Apr 16. pii: 2026.04.14.26350906. [Epub ahead of print]

Transcriptomic Profiling in Skeletal Muscle Identifies Associations With Knee Osteoarthritis: the Study of Muscle, Mobility and Aging (SOMMA).

Daniel S Evans, Tyler A Mansfield, Gina M Many, Tyler J Sagendorf, Samaneh Farsijani, Bret H Goodpaster, Lauren M Sparks, Nancy E Lane.

Objectives: The association between skeletal muscle gene expression and knee osteoarthritis (OA) was examined among older adult participants of the Study of Muscle, Mobility and Aging (SOMMA).
Methods: Inclusion criteria included knee radiographs and bulk RNA sequencing (RNAseq) in vastus lateralis muscle, resulting in 523 participants (56% female). Radiographic knee OA was determined by Kellgren-Lawrence (KL) grades. Differential gene expression was analyzed using a control group (KL ≤ 1, n = 326) and two nested case groups: (a) KL ≥ 2 (n = 197), (b) KL ≥ 3 (n = 112).
Results: Compared with controls, there were 27 and 41 genes associated (FDR ≤ 0.05) with KL ≥ 2 and KL ≥ 3, respectively, and 16 genes significantly associated in both contrasts. For 15 of the 16 genes, the association magnitude was larger with more severe OA (KL ≥ 3). Genes associated in both contrasts included brain-derived neurotrophic factor (BDNF) and interferon regulatory factor-2 (IRF2). Gene sets enriched in KL ≥ 2 and KL ≥ 3 contrasts included DNA repair and branched chain amino acid (BCAA) catabolism.
Conclusions: Our results in older adult SOMMA participants indicate that knee OA is associated with genes and pathways expressed in skeletal muscle that are involved in pain sensitization, BCAA catabolism, muscle function preservation, calcium transport and storage, inflammation, and extracellular matrix remodeling. Additional longitudinal studies will be needed to determine how these genes could affect the progression of knee OA.

DOI: https://doi.org/10.64898/2026.04.14.26350906

Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2528281123

Mitochondrial double-stranded RNA fuels pancreatic cancer growth via RIG-I/TLR3 inflammation.

Andrew T Milcarek, Minjeong Yeon, Camilla Esposito, Prerna Kulkarni, Andrew V Kossenkov, Jozef Madzo, Anneliese M Faustino, Hsin-Yao Tang, Alessandra M Storaci, Alessandro Palleschi, Marco Locatelli, Valentina Vaira, Mary V Iacocca, Andrea Ward, Arvind Sabesan, Nicholas J Petrelli, Michela Perego, Dario C Altieri.

Mitochondria activate inflammation and innate immunity to protect against infections, but the role in cancer is unknown. Here, we report that patients with pancreatic ductal adenocarcinoma (PDAC) with reduced levels of the mitochondrial scaffold, Mic60, or inner mitochondrial membrane protein, exhibit increased inflammation, high NFκB activity and production of TNFα. This is mediated by double-stranded RNA (dsRNA) released from structurally defective, Mic60-low mitochondria, which engages TLR3/RIG-I sensing, activates NFκB gene expression and reprograms transcriptional and signaling networks to promote PDAC proliferation. Preclinical targeting of mitochondrial dsRNA signaling triggers rapid cell death and inhibition of tumor growth, selectively in Mic60-knockdown PDAC, without overt toxicity, in vivo. Therefore, dsRNA released from defective mitochondria generates protumorigenic inflammation and provides an actionable therapeutic target in selected PDAC patients.

Keywords: TLR3; dsRNA; inflammation; pancreatic cancer; viral mimicry

DOI: https://doi.org/10.1073/pnas.2528281123

bioRxiv. 2026 Apr 15. pii: 2026.04.14.718098. [Epub ahead of print]

Synapse specific alterations of autophagy are a hallmark of Danon disease.

Beatrice Terni, Maria Quiles-Pastor, Zoë Reynolds, Kelsey Coppenrath, Nikko-Ideen Shaidani, Pablo Martínez San Segundo, Shawn Adam, Nicolás Riffo-Lepe, Zachary Smith, Marko Horb, Carlos Aizenman, Artur Llobet.

Danon disease is a rare disorder caused by mutations in the LAMP2 gene, which encodes a lysosomal membrane protein key to the endolysosomal pathway and autophagy. Affected individuals show multisystemic alterations that include cardiomyopathy, skeletal muscle weakness, visual deficits and cognitive impairment. Here we establish a knockout LAMP2 line in Xenopus tropicalis that reproduces the characteristic cardiac activity, mobility impairments and vision deficits present in the disease. Damaged mitochondria were abundantly found in skeletal muscle fibers. LAMP2 mutant X. tropicalis detected light with a reduced preference for green wavelengths. Visual deficits were consistent with the finding of damaged mitochondria in the inner segment of rods but not in cones. Differences in autophagic flux were found in presynaptic terminals from photoreceptors and olfactory sensory neurons (OSNs), which establish the first synapse processing vision and olfaction, respectively. In wild-type animals autophagic shapes were observed in OSN terminals but were absent from photoreceptor ribbon synapses. In knockout LAMP2 tadpoles, autophagic organelles covered 7% of the OSN presynaptic terminal surface, a three-fold increase compared to photoreceptor terminals. These differences suggest that LAMP2 plays synapse-specific roles that could be an important determinant of the psychiatric manifestations present in Danon disease and support the use of LAMP2 X. tropicalis to shed new light on the pathological bases of this lysosomal storage disorder.

DOI: https://doi.org/10.64898/2026.04.14.718098