MicroRNA-195 Regulates Metabolism in Failing Myocardium Via Alterations in Sirtuin 3 Expression and Mitochondrial Protein Acetylation

Abstract

Altogether, these data suggest that increased levels of miR-195 in failing myocardium regulate a novel pathway that involves direct SIRT3 suppression and enzymatic inhibition via increased acetylation of PDH and ATP synthase that are essential for cardiac energy metabolism.

Mitochondrial dysfunction in pathophysiology of heart failure

“…The most studied modification is acetylation, although modifications by other acyl-CoAs also occur in the mitochondria (Figure 3). Increased mitochondrial protein acetylation has been found in the failing hearts of animal models and patients (74)(75)(76)(77)(78). A large number of proteins, including those involved in substrate oxidation, e.g., pyruvate dehydrogenase and fatty acid oxida-tion of glucose.…”

“…SIRT4 and SIRT5 have weak deacetylase function but possess demalonylase and desuccinylase activities or ADP-ribosylation function (73). Downregulation of SIRT3 has been shown in the failing heart (78,85). Furthermore, sirtuin activity is dependent on NAD + availability.…”

“…A lower NAD + /NADH ratio decreases enzymatic activities for substrate tion enzymes, TCA cycle enzymes, and ETC proteins, have been shown to be hyperacetylated (75,76). Protein hyperacetylation has been shown to decrease activities of succinate dehydrogenase, pyruvate dehydrogenase, ATP synthase, and malate-aspartate shuttle enzymes; additionally, hyperacetylation of oligomycin sensitivity-conferring protein (OSCP) increased the sensitivity to mPTP opening (75,76,(78)(79)(80)(81)(82). Moreover, inhibition of malateaspartate shuttle by acetylation impairs the transport of cytosolic NADH into mitochondria, thereby disrupting cytosolic redox state and glycolytic ATP production during the transition from cardiac hypertrophy to failure (76,83).…”

“…Stimulation of mitochondrial respiration for ATP production is associated with increased ROS generation due to increased ETC activity. Running counter to the notion that increased energy demand in the chronically stressed heart should stimulate mitochondrial ATP synthesis, recent studies suggest that ATP synthase activity is inhibited in the failing heart because of increased protein acetylation (78). Inhibition of ATP synthase activity not only impedes ATP production but also impairs electron flow and enhances ROS emission (128,129).…”

Mitochondrial MiRNA in Cardiovascular Function and Disease

“…For example, miR-195 induction was found to be along with decreased expression of mitochondrial deacetylase SIRT3 in failing human myocardium [76]. MiR-195 downregulated SIRT3 expression through direct 3 -UTR targeting in AC16 human cardiomyocyte-like cells, and MiR-195 KO transgenic mice exhibited reduced SIRT3 expression levels associated with hyperacetylation of key metabolic enzymes and energy depletion, leading to cardiac remodeling and heart failure [76]. It is intriguing to explore the possibility of more nuclear-encoded mitomiRs in mediating nuclear-mitochondria communication mechanisms underlying mitochondria-relevant diseases.…”