Revealing the mitochondrial diseases-associated immune dysfunctions – MAID

Mitochondrial diseases result from deficiencies of oxidative phosphorylation due to mutations of nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). They are challenging genetic disorders owing to marked clinical variations seen in patients and the variety of organs that can be affected. Strikingly, despite the fact that mitochondria are critical bioenergetic organelles whose functional adaptations are closely associated with immune cell activation, immune alterations associated with mitochondrial diseases are poorly described. The main hurdles for understanding the immunological consequences of genetic mitochondrial diseases are posed by the immune system’s complexity and the co-existence of mutant and non-mutant mtDNA within the same cells, a phenomenon called heteroplasmy. Here, we team-up in a French-German consortium to devise single-cell sequencing technologies to 1) characterize alterations of immune parameters and immune cell populations linked to mitochondrial disorders in humans, and to 2) define functional outcomes of mtDNA heteroplasmy on a cellular level in immune cells. For this, we will capitalize on a unique clinical cohort of patients with mitochondrial diseases in the University-Hospital of Bordeaux, implement a novel approach to combine mtDNA and RNA sequencing with single cell resolution to evaluate heteroplasmy-linked transcriptome alterations and assess immunological and metabolic functions in monocytes, T and B lymphocytes. This study offers a unique opportunity to determine whether mitochondrial function is linked to immune cell functions in humans by bypassing hurdles linked to heteroplasmy and may reveal therapeutic targets and novel clinical diagnostic markers for mitochondrial disorders.