Human
mitochondrial disorders impact tissues with high energetic demands and can be associated with cardiac muscle disease (
cardiomyopathy) and early mortality. However, the mechanistic link between
mitochondrial disease and the development of
cardiomyopathy is frequently unclear. In addition, there is often marked phenotypic heterogeneity between patients, even between those with the same genetic variant, which is also not well understood. Several of the mitochondrial
cardiomyopathies are related to defects in the maintenance of
mitochondrial protein homeostasis, or proteostasis. This essential process involves the importing, sorting, folding and degradation of preproteins into fully functional mature structures inside mitochondria. Disrupted mitochondrial proteostasis interferes with mitochondrial energetics and
ATP production, which can directly impact cardiac function. An inability to maintain proteostasis can result in
mitochondrial dysfunction and subsequent mitophagy or even apoptosis. We review the known
mitochondrial diseases that have been associated with
cardiomyopathy and which arise from mutations in genes that are important for mitochondrial proteostasis. Genes discussed include DnaJ
heat shock protein family member C19 (DNAJC19), mitochondrial import inner membrane translocase subunit TIM16 (MAGMAS), translocase of the inner mitochondrial membrane 50 (TIMM50),
mitochondrial intermediate peptidase (MIPEP),
X-prolyl-aminopeptidase 3 (XPNPEP3), HtraA
serine peptidase 2 (HTRA2), caseinolytic mitochondrial
peptidase chaperone subunit B (CLPB) and heat shock 60-kD
protein 1 (HSPD1). The identification and description of disorders with a shared mechanism of disease may provide further insights into the disease process and assist with the identification of potential
therapeutics.