Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure

Abstract

Mitochondrial (mt) DNA depletion and oxidative mtDNA damage have been implicated in the process of pathological cardiac remodeling. Whether these features are present in the early phase of maladaptive cardiac remodeling, that is, during compensated cardiac hypertrophy, is still unknown.We compared the morphologic and molecular features of mt biogenesis and markers of oxidative stress in human heart from adult subjects with compensated hypertrophic cardiomyopathy and heart failure. We have shown that mtDNA depletion is a constant feature of both conditions. A quantitative loss of mtDNA content was associated with significant down-regulation of selected modulators of mt biogenesis and decreased expression of proteins involved in mtDNA maintenance. Interestingly, mtDNA depletion characterized also the end-stage phase of cardiomyopathies due to a primary mtDNA defect. Oxidative stress damage was detected only in failing myocardium.

Postnatal Hyperoxia Exposure Durably Impairs Right Ventricular Function and Mitochondrial Biogenesis

“…Interestingly, loss of mitochondrial DNA content has been shown to downregulate modulators of mitochondrial biogenesis, beginning during RV hypertrophy and progressing further with the onset of RV failure (41,42). Complete loss of COX activity has previously been suggested to occur when mutation abundance surpasses 90% of the total mitochondrial genome (26), which would suggest a relatively high burden of mitochondrial DNA damage in Hx animals, particularly males.…”

Mitochondrial function in the heart: the insight into mechanisms and therapeutic potentials

“…Under high‐fat‐diet stress, the ERK5‐MEF2 pathway is active to maintain PGC1α expression for preserving mitochondrial integrity (Liu et al ., ). Of note, a depressed PGC1α transcriptional network is a feature of heart failure induced by pressure overload (Garnier et al ., ) or myocardial infarction, and it correlates with a reduced mitochondrial respiratory capacity, even when mitochondrial mass is not decreased, which is observed in human hypertrophic myocardium and ischaemic‐induced failing heart (Pisano et al ., ) (Figure ).…”

Metabolic Alterations in Inherited Cardiomyopathies

“…Treatment with ROS scavengers (e.g., N-acetylcysteine, NAC) in HCM models show positive effects on cardiac function, accompanied by the reduction of ventricular hypertrophy, fibrosis, and myocyte disarray [84][85][86]. Accordingly, in symptomatic HCM patients, lower catalase activity is observed, while the levels of other antioxidant enzymes, including mitochondrial superoxide dismutase (SOD) and glutathione peroxidase (GPX), are unaltered [87]. Similar findings were reported in a pig model of naturally occurring HCM [88].…”