Biology subjects

Marmyleva, A.

Publications and source records attributed to Marmyleva, A..

3 recordsLinked to original sources

bioRxiv2026

GDF15 modifies NAD+ salvage pathway and dampens immune response in mitochondrial disease

Mitochondrial integrated stress response (ISRmt) is a main mammalian metabolic stress pathway, with local ISRmt and a systemic response via circulating metabokines GDF15 and FGF21 as early signs of the response in mitochondrial diseases. FGF21 has been reported to regulate ISRmt progression and nutrient homeostasis, but the roles of GDF15 have remained unclear. Here, we explored the effects of inactivation of FGF21 or GDF15 or them together in Deletor mice. These mice endogenously activate the full ISRmt and metabokines as part of their mitochondrial muscle disease. GDF15 inactivity upregulated the skeletal muscle enzyme NMRK2, which converts nicotinamide riboside (NR) to nicotinamide mononucleotide (NMN) and NAD+. FGF21 was required for glutathione homeostasis. GDF15 inactivation also induced immune cell invasion in the muscle, aggravated by FGF21 loss, suggesting synergistic anti-inflammatory effects. Our findings indicate that in addition to their systemic effects, FGF21 and GDF15 are autocrine controllers of redox homeostasis in mitochondrial disease muscle.

cell biology↗

bioRxiv2026

Mitochondrial dysfunction reshapes methyl-group allocation inskeletal muscle

Mitochondria are central metabolic organelles with functions extending beyond energy production to anabolic and folate-mediated one-carbon (1C) metabolism. One-carbon metabolism supports methylation reactions that modify diverse targets including metabolites, nucleic acids, and chromatin, and has emerged as a contributor to mitochondrial disease-related stress responses. Here, we report tissue-specific remodeling of methylation events in response to mtDNA replication defect, using the deletor mice carrying a dominant mutation in Twinkle, the replicative helicase of mtDNA, causing adult-onset mitochondrial myopathy (MM) in humans and mice. In affected skeletal muscle, deletors show a distinct methylation signature, with increased creatine synthesis and reduced phosphatidylcholine production, two major consumers of S-adenosylmethionine-derived methyl groups. We further observed tissue-specific upregulation of selected RNA methylation marks and redistribution of the repressive histone mark H3K9me3, indicating coordinated remodeling of metabolic and epigenetic methylation pathways. Our evidence shows that a mtDNA replication defect remodels muscle-specific methylation signature of phospholipids, histones and RNA, identifying methylation remodeling as a key component of MM pathogenesis.

molecular biology↗

bioRxiv2023

De novo serine biosynthesis is protective in mitochondrial disease

Importance of serine as a metabolic regulator is well known in tumors and raising attention also in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of 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 mitochondrial integrated stress response (ISRmt), 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 the skeletal muscle. Bullet pointsO_LISerine becomes an essential amino acid in mitochondrial translation defects C_LIO_LIBlocking de novo serine biosynthesis promotes progression of mitochondrial disease C_LIO_LIDe novo serine biosynthesis maintains phospholipid homeostasis upon mitochondrial insult C_LIO_LISerine biosynthesis sustains redox-balance and mitochondrial translation in disease C_LI

cell biology↗