Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases

The association between certain mitochondrial DNA variants and increased risk of late-onset diseases in humans could be explained by a direct role of mitochondrial DNA in the regulation of cellular proteostasis. Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis.

Automated summary

Certain mitochondrial DNA variants may increase the risk of late-onset diseases by regulating cellular proteostasis. Variants defining mitochondrial DNA haplogroups Uk and H4 modulate the level of N-formylmethionine, affecting mitochondrial protein translation and influencing the risk of age-related diseases by affecting cell proteostasis.