Mutyh deficiency downregulates mitochondrial fusion proteins and causes cardiac dysfunction via α-ketoglutaric acid reduction with oxidative stress

Abstract

MutY homolog (MUTYH), an important protein in base excision repair (BER) system, excises adenine in the nascent strand opposite 8-oxoguanine in template DNA and restores G:C base-pair to maintain the fidelity of DNA replication. The loss of MUTYH causes oxidative stress and influences cardiac function, but the mechanism remains to be addressed. Here we demonstrate that Mutyh deficiency alters mitochondrial structure and impairs mitochondrial function through downregulation of mitochondrial fusion protein Mfn2 and alteration of the ratio of L-Opa1/S-Opa1 accompanied by reduction of α-ketoglutaric acid (α-KG) under oxidative stress condition. Further analysis reveals that the Mutyh deficiency may cause downregulation of histone demethylases and DNA demethylases and inhibition of the Mfn2 transcription. Oxidative stress associated with tert-butyl hydroperoxide (t-BHP) exposure results in the degradation of L-Opa1 and impairs the balance of L-Opa1/S-Opa1. Interestingly, α-KG supplementation alleviates the damage associated with Mutyh deficiency, restores the expression of Mfn2 and prevents degradation of L-Opa1. The current study demonstrates the relationship among Mutyh deficiency-coupled oxidative stress, the altered expressions of Mfn2 and Opa1, and the mitochondrial dysfunction, in which an intermediate in the tricarboxylic acid (TCA) cycle, α-KG has a key regulatory role.