Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups

TLDR

Human mitochondrial haplogroups have been linked to both rare mitochondrial diseases and common age‑related disorders, yet mechanistic evidence is scarce and the small, context‑dependent effects of haplogroup‑defining mutations on oxidative phosphorylation remain poorly understood. The study aims to standardize the cellular context of mtDNA mutations by employing cybrid cell lines. Cybrids, which combine a common nuclear background with distinct mitochondrial genomes, were used to compare OXPHOS parameters across haplogroups. Cybrid comparisons revealed that haplogroup H cells exhibit higher mtDNA/mRNA levels, protein synthesis, cytochrome oxidase activity, oxygen consumption, membrane potential, and growth than haplogroup Uk, indicating inherited OXPHOS differences that may underlie susceptibility to complex disorders and suggest a new field of mitochondrial pharmacogenomics.

Abstract

Many epidemiologic studies have associated human mitochondrial haplogroups to rare mitochondrial diseases like Leber's hereditary optic neuropathy or to more common age-linked disorders such as Parkinson's disease. However, cellular, biochemical and molecular-genetic evidence that is able to explain these associations is very scarce. The etiology of multifactorial diseases is very difficult to sort out because such diseases are due to a combination of genetic and environmental factors that individually only contribute in small part to the development of the illness. Thus, the haplogroup-defining mutations might behave as susceptibility factors, but they could have only a small effect on oxidative phosphorylation (OXPHOS) function. Moreover, these effects would be highly dependent on the 'context' in which the genetic variant is acting. To homogenize this 'context' for mitochondrial DNA (mtDNA) mutations, a cellular approach is available that involves the use of what is known as 'cybrids'. By using this model, we demonstrate that mtDNA and mtRNA levels, mitochondrial protein synthesis, cytochrome oxidase activity and amount, normalized oxygen consumption, mitochondrial inner membrane potential and growth capacity are different in cybrids from the haplogroup H when compared with those of the haplogroup Uk. Thus, these inherited basal differences in OXPHOS capacity can help to explain why some individuals more quickly reach the bioenergetic threshold below which tissue symptoms appear and progress toward multifactorial disorders. Hence, some population genetic variants in mtDNA contribute to the genetic component of complex disorders. The existence of mtDNA-based OXPHOS differences opens possibilities for the existence of a new field, mitochondrial pharmacogenomics.