Physiological and molecular characterization of individuals carrying a diabetogenic mtDNA mutation establishes a mitochondrial basis for insulin resistance in humans

Mitochondrial dysfunction has long been associated with insulin resistance, yet the causal relationship in humans remains unresolved. Here, we leveraged individuals carrying the diabetogenic m.3243A>G mtDNA mutation as a human genetic model to probe the causal contribution of mitochondrial defects to insulin resistance and delineate the underlying molecular and bioenergetic mechanisms. In vivo metabolic phenotyping revealed selective skeletal muscle insulin resistance with preserved liver and adipose insulin sensitivity, accompanied by impaired glucose tolerance, {beta}-cell dysfunction, and elevated circulating levels of the mitochondrial stress-responsive cytokine GDF15. At the molecular level, this muscle-specific insulin-resistant phenotype featured preserved insulin-stimulated Akt-TBC1D4 signaling but blunted mTORC1 activation. Integrated muscle proteomic and bioenergetic profiling demonstrated reduced mitochondrial protein abundance and complex I-specific molecular and functional impairments, alongside downregulation of non-mitochondrial metabolic proteins including AMPK{gamma}2. In summary, our study establishes a mitochondrial basis for insulin resistance in humans, linking reduced mitochondrial content and complex I-related defects to disrupted mTORC1 signaling and impaired muscle insulin action. These findings highlight mitochondria-dependent molecular signatures of insulin resistance that may hold translational relevance for improving glucose regulation in common metabolic diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/25342274v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@7b7f35org.highwire.dtl.DTLVardef@1dc7a0dorg.highwire.dtl.DTLVardef@1d121c7org.highwire.dtl.DTLVardef@10094da_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG