Heart failure in patients is associated with downregulation of mitochondrial quality control genes

Abstract

BackgroundMitochondrial dysfunction is one of key factors causing heart failure. We performed a comprehensive analysis of expression of mitochondrial quality control (MQC) genes in heart failure.MethodsMyocardial samples were obtained from patients with ischemic and dilated cardiomyopathy in a terminal stage of heart failure and donors without heart disease. Using quantitative real‐time PCR, we analysed a total of 45 MQC genes belonging to mitochondrial biogenesis, fusion‐fission balance, mitochondrial unfolded protein response (UPRmt), translocase of the inner membrane (TIM) and mitophagy. Protein expression was analysed by ELISA and immunohistochemistry.ResultsThe following genes were downregulated in ischemic and dilated cardiomyopathy: COX1, NRF1, TFAM, SIRT1, MTOR, MFF, DNM1L, DDIT3, UBL5, HSPA9, HSPE1, YME1L, LONP1, SPG7, HTRA2, OMA1, TIMM23, TIMM17A, TIMM17B, TIMM44, PAM16, TIMM22, TIMM9, TIMM10, PINK1, PARK2, ROTH1, PARL, FUNDC1, BNIP3, BNIP3L, TPCN2, LAMP2, MAP1LC3A and BECN1. Moreover, MT‐ATP8, MFN2, EIF2AK4 and ULK1 were downregulated in heart failure from dilated, but not ischemic cardiomyopathy. VDAC1 and JUN were only genes that exhibited significantly different expression between ischemic and dilated cardiomyopathy. Expression of PPARGC1, OPA1, JUN, CEBPB, EIF2A, HSPD1, TIMM50 and TPCN1 was not significantly different between control and any form of heart failure. TOMM20 and COX proteins were downregulated in ICM and DCM.ConclusionsHeart failure in patients with ischemic and dilated cardiomyopathy is associated with downregulation of large number of UPRmt, mitophagy, TIM and fusion‐fission balance genes. This indicates multiple defects in MQC and represents one of potential mechanisms underlying mitochondrial dysfunction in patients with heart failure.

Low Level of First Morning Urine Cardiac Troponin I: A Specific Hallmark of Aortic Stenosis Severity

“…Having to overcome higher pressure, the cardiomyocytes thicken, causing hypertrophy of cellular contractile elements. This increased volume of cardiomyocytes causes increased energy consumption and mitochondrial dysfunction, which leads to further cellular energy insufficiency [20]. The need for cardiomyocytes to generate stronger contractile forces increases cellular calcium levels.…”

OPA1, a molecular regulator of dilated cardiomyopathy

“…47 However, a recent study has shown that the OMA1 gene is downregulated in studies of dilated cardiomyopathy, but there is no significant difference in OPA1 compared to the control group. 50 Specific ablation of cardiac Yme1L in mice to activate OMA1 accelerates OPA1 proteolysis, triggering mitochondrial fragmentation and altering cardiometabolic, leading to dilated cardiomyopathy. 48 OPA1 is mainly involved in the IM fusion part of mitochondrial dynamics.…”