image: Mitochondrial DNA (mtDNA) mutations impair OXPHOS and enhance lactate accumulation in skeletal muscle. Elevated lactate drives H3K14 histone lactylation, inducing GDF15 expression and secretion in mitochondrial myopathy.
Credit: ©Science China Press
Growth differentiation factor 15 (GDF15) has emerged as a reliable biomarker of mitochondrial myopathy, a group of inherited disorders caused by mitochondrial DNA (mtDNA) mutations. However, where GDF15 comes from and how its production is regulated have remained unanswered questions—until now.
Researchers at Qilu Hospital of Shandong University have uncovered a novel mechanism by which skeletal muscle under mitochondrial stress drives GDF15 secretion. Their findings reveal that lactate, commonly known as a byproduct of glycolysis, acts as a signaling molecule to induce histone lactylation, an epigenetic modification that activates GDF15 gene expression.
Using patient muscle biopsies, cultured myoblasts carrying mtDNA mutations, and hypoxia-induced stress models, the team demonstrated that impaired oxidative phosphorylation in muscle cells increases lactate production. Elevated lactate triggers histone lactylation, particularly at histone H3K14, which in turn promotes transcription and secretion of GDF15. Blocking lactate accumulation or inhibiting histone lactylation enzymes markedly reduced GDF15 levels, confirming a causal relationship.
The study not only establishes skeletal muscle as a key source of circulating GDF15 in mitochondrial myopathy but also identifies lactate-driven histone lactylation as the molecular switch controlling its production. This mechanism may also explain why external stressors such as hypoxia intensify GDF15 expression, supporting the “second-hit” hypothesis in disease progression.
“By linking lactate metabolism to epigenetic regulation, we uncovered how mitochondrial dysfunction in muscle translates into a systemic biomarker signal,” the authors noted. “These findings highlight lactate-driven histone lactylation as a potential therapeutic target in mitochondrial myopathy.”
Beyond mitochondrial myopathy, the discovery sheds light on how stress-responsive myokines like GDF15 orchestrate whole-body metabolic adaptation. It also underscores the broader concept that metabolites such as lactate can directly influence gene regulation through epigenetic pathways.
This breakthrough paves the way for future research into metabolic-epigenetic crosstalk in human disease and may open new avenues for therapeutic interventions targeting GDF15 regulation.
The Department of Neurology at Qilu Hospital of Shandong University, together with Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, has been a national leader in neuromuscular pathology and rare disease research since the 1980s in China. The team has biobanks of muscle and nerve biopsy samples and pioneered molecular and functional diagnostic platforms. Their work has advanced the understanding of mitochondrial and neuromuscular diseases and provided critical diagnostic and training resources nationwide.
Journal
Science Bulletin