記述言語：英語   掲載種別：研究論文（学術雑誌）  

<h4>Background</h4>Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual-extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles-respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.<h4>Methods</h4>We used a mouse model for mitochondrial myopathy ("deletor"), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.<h4>Results</h4>In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.<h4>Conclusions</h4>Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.

DOI： 10.1002/ctm2.70404

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cell Reports  

The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISR^mt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.

DOI： 10.1016/j.celrep.2025.115710

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature  

<jats:title>Abstract</jats:title><jats:p>Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response<jats:sup>1–4</jats:sup>. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (<jats:italic>POLG1</jats:italic>)<jats:sup>5</jats:sup>. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms<jats:sup>5</jats:sup>, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals<jats:sup>6</jats:sup> demonstrates enrichment of immunodeficient traits in carriers of the <jats:italic>POLG1</jats:italic> p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.</jats:p>

DOI： 10.1038/s41586-024-07260-z

Scopus

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cell Metabolism  

Mitophagy is a quality control mechanism that eliminates damaged mitochondria, yet its significance in mammalian pathophysiology and aging has remained unclear. Here, we report that mitophagy contributes to mitochondrial dysfunction in skeletal muscle of aged mice and human patients. The early disease stage is characterized by muscle fibers with central nuclei, with enhanced mitophagy around these nuclei. However, progressive mitochondrial dysfunction halts mitophagy and disrupts lysosomal homeostasis. Interestingly, activated or halted mitophagy occur in a mosaic manner even in adjacent muscle fibers, indicating cell-autonomous regulation. Rapamycin restores mitochondrial turnover, indicating mTOR-dependence of mitochondrial recycling in advanced disease stage. Our evidence suggests that (1) mitophagy is a hallmark of age-related mitochondrial pathology in mammalian muscle, (2) mosaic halting of mitophagy is a mechanism explaining mosaic respiratory chain deficiency and accumulation of pathogenic mtDNA variants in adult-onset mitochondrial diseases and normal aging, and (3) augmenting mitophagy is a promising therapeutic approach for muscle mitochondrial dysfunction.

DOI： 10.1016/j.cmet.2021.12.017

Scopus