Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity

Abstract

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with a likely oligogenic etiology, but our understanding of the genetic complexities and pathogenic mechanisms leading to HLHS is limited. We therefore performed whole genome sequencing (WGS) on a large cohort of HLHS patients and their families to identify candidate genes that were then tested in Drosophila heart model for functional and structural requirements. Bioinformatic analysis of WGS data from an index family comprised of a HLHS proband born to consanguineous parents and postulated to have a homozygous recessive disease etiology, prioritized 9 candidate genes with rare, predicted damaging homozygous variants. Of the candidate HLHS gene homologs tested, cardiac-specific knockdown (KD) of mitochondrial MICOS complex subunit dCHCHD3/6 resulted in drastically compromised heart contractility, diminished levels of sarcomeric actin and myosin, reduced cardiac ATP levels, and mitochondrial fission-fusion defects. Interestingly, these heart defects were similar to those inflicted by cardiac KD of ATP synthase subunits of the electron transport chain (ETC), consistent with the MICOS complex's role in maintaining cristae morphology and ETC complex assembly. Analysis of 183 genomes of HLHS patient-parent trios revealed five additional HLHS probands with rare, predicted damaging variants in CHCHD3 or CHCHD6. Hypothesizing an oligogenic basis for HLHS, we tested 60 additional prioritized candidate genes in these cases for genetic interactions with CHCHD3/6 in sensitized fly hearts. Moderate KD of CHCHD3/6 in combination with Cdk12 (activator of RNA polymerase II), RNF149 (E3 ubiquitin ligase), or SPTBN1 (scaffolding protein) caused synergistic heart defects, suggesting the potential involvement of a diverse set of pathways in HLHS. Further elucidation of novel candidate genes and genetic interactions of potentially disease-contributing pathways is expected to lead to a better understanding of HLHS and other CHDs.

Mitochondrial Structure and Function in Human Heart Failure

“… 171 , 185 Rare variants in MIC19 and MIC25 are associated with hypoplastic left heart syndrome. 193 Consistent with a causal role, depletion of Mic19 in the Drosophila heart compromises heart function, decreases ATP, and results in the accumulation of mitochondrial aggregates, suggestive of altered mitochondrial dynamics. 193 In mammals, knockout of either MIC10 or MIC60 results in a reduction in maximal mitochondrial respiration.…”

“… 193 Consistent with a causal role, depletion of Mic19 in the Drosophila heart compromises heart function, decreases ATP, and results in the accumulation of mitochondrial aggregates, suggestive of altered mitochondrial dynamics. 193 In mammals, knockout of either MIC10 or MIC60 results in a reduction in maximal mitochondrial respiration. 171 , 173 , 185 However, it is not known whether there are differences in MICOS complex expression across different types of HF (Figure 1 ) or whether only certain MICOS complex subunits are essential for stability in HF.…”

The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney

“…The role of the MICOS complex in disease states remains more controversial. Generally, loss of the MICOS complex has been shown to reduce cardiac ATP levels, thus impairing tissue integrity 95 . Studies within other tissue types, such as the liver have shown that Chchd3 depletion results in impaired MERCs to induce fatty liver disease with SLC25A46 involvement 96 .…”

ERBB2 R599C variant is associated with left ventricular outflow tract obstruction defects in human

“…PRKCI is required for heart trabeculation in mice (57), PIK3R2 regulates heart size and hypertrophy in mice (58), PIK3CB promotes CM proliferation and survival in neonatal rat CMs (59) and PRKCA regulates heart contractility in mice (60). In addition, the ERBB2 R599C receptor had reduced interaction with proteins such as SOS1, PTPN11, CBL, which have been associated with syndromic CHD (61, 62) (63) and MICOS13, DTNA, and EMC1 which have been associated with nonsyndromic CHD (64) (65, 66). In addition, the mutant receptor has lost interaction with FRS2, and Frs2alpha is required for outflow tract morphogenesis (67).…”