Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

Members of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family that carry (CX9C) type motifs are imported into the mitochondrion with the help of the disulfide relay-dependent MIA import pathway. These evolutionarily conserved proteins are emerging as new cellular factors that control mitochondrial respiration, redox regulation, lipid homeostasis, and membrane ultrastructure and dynamics. We discuss recent insights on the activity of known (CX9C) motif-carrying proteins in mammals and review current data implicating the Mia40/CHCHD4 import machinery in the regulation of their mitochondrial import. Recent findings and the identification of disease-associated mutations in specific (CX9C) motif-carrying proteins have highlighted members of this family of proteins as potential therapeutic targets in a variety of human disorders.

TrendsThe bioenergetic and metabolic activities of the mitochondrion are crucial for cellular survival and adaptation to stress.The vast majority of mitochondrial proteins are encoded by the nuclear genome and hence must be imported.In humans, dysfunction of the mitochondrial protein import process has been associated with mitochondriopathies, neurodegeneration, diabetes, aging, and cancer.The import of small cysteine motif-carrying proteins into the mitochondrial intermembrane space is controlled by the phylogenetically conserved disulfide relay-dependent Mia40/CHCHD4 import machinery.This import machinery interacts with a variety of proteins, many of which contain CHCH domains, the CHCHD proteins.In humans, CHCHD4 substrates constitute an emerging class of disease-associated proteins.