Mitochondrial Complex I Deficiency Increases Protein Acetylation and Accelerates Heart Failure

Abstract

Summary Mitochondrial respiratory dysfunction is linked to the pathogenesis of multiple diseases including heart failure but the specific mechanisms for this link remain largely elusive. We modeled the impairment of mitochondrial respiration by inactivation of the Ndufs4 gene, a protein critical for Complex I (C-I) assembly, in the mouse heart (cKO). While C-I supported respiration decreased by >40%, the cKO mice maintained normal cardiac function in vivo and high-energy phosphate content in isolated perfused hearts. However, the cKO mice developed accelerated heart failure after pressure overload or repeated pregnancy. Decreased NAD+/NADH ratio by C-I deficiency inhibited Sirt3 activity, leading to increase in protein acetylation, and sensitization of the permeability transition in mitochondria (mPTP). NAD+ precursor supplementation to cKO mice partially normalized the NAD+/NADH ratio, protein acetylation and mPTP sensitivity. These findings describe a mechanism connecting mitochondrial dysfunction to the susceptibility to diseases and propose a potential therapeutic target.

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

“…Similarly, genetic complex-I deficiency in mouse embryonic fibroblasts from NDUFS4 −/− mice is characterized by lower cellular levels of NAD + and increased levels of NADH (leading to a reduced NAD + :NADH ratio), without alterations in NADP + and NADPH levels (Valsecchi et al, 2012). Using a heart-specific NDUFS4 −/− mouse model, further evidence has been provided that complex-I deficiency is associated with a reduced NAD ratio and that this reduction is paralleled by a lower activity of the NAD + -dependent deacetylase sirtuin 3 (Sirt3) (Karamanlidis et al, 2013). As a consequence, protein acetylation is increased and heart failure accelerated.…”

Calorie restriction and sirtuins revisited

“…In this case, SIRT6 serves as a corepressor of IGF-activated genes by binding to the transcription factor c-jun. Finally, a new study shows that mice knocked out for one subunit of complex I in the heart show a buildup of NADH, inactivation of SIRT3, and the hyperacetylation of cardiac mitochondrial proteins (Karamanlidis et al 2013). These mice are much more susceptible to heart failure, reinforcing the established importance of SIRT3 in cardiac function (Pillai et al 2010).…”

Mitochondrion as a Target for Heart Failure Therapy – Role of Protein Lysine Acetylation –

“…76, 80 Treatment of the heart with complex I deficiency with the NAD + precursor NMN normalizes NAD + / NADH ratio and restores the sensitivity of mPTP to calcium challenge. 92 NMN treatment also attenuates diet-/age-induced diabetes 76 and the effects of aging. 77 Elevating NAD + via another NAD + precursor, NR, protects mice from high fat dietinduced obesity.…”