Functional interactions between complex I and complex II with nNOS in regulating cardiac mitochondrial activity in sham
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MUSCLE PHYSIOLOGY
Functional interactions between complex I and complex II with nNOS in regulating cardiac mitochondrial activity in sham and hypertensive rat hearts Yu Na Wu 1,2 & Vidya K Sudarshan 3,4 & Shi Chao Zhu 5 & Yong Feng Shao 6 & Sung Joon Kim 2 & Yin Hua Zhang 1,2,7 Received: 1 May 2020 / Revised: 6 August 2020 / Accepted: 2 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Nitric oxide (NO) affects mitochondrial activity through its interactions with complexes. Here, we investigated regulations of complex I (C-I) and complex II (C-II) by neuronal NO synthase (nNOS) in the presence of fatty acid supplementation and the impact on left ventricular (LV) mitochondrial activity from sham and angiotensin II (Ang-II)– induced hypertensive (HTN) rats. Our results showed that nNOS protein was expressed in sham and HTN LV mitochondrial enriched fraction. In sham, oxygen consumption rate (OCR) and intracellular ATP were increased by palmitic acid (PA) or palmitoyl-carnitine (PC). nNOS inhibitor, S-methyl-l-thiocitrulline (SMTC), did not affect OCR or cellular ATP increment by PA or PC. However, SMTC increased OCR with PA + malonate (a C-II inhibitor), but not with PA + rotenone (a C-I inhibitor), indicating that nNOS attenuates C-I with fatty acid supplementation. Indeed, SMTC increased C-I activity but not that of C-II. Conversely, nNOS-derived NO was increased by rotenone + PA in LV myocytes. In HTN, PC increased the activity of C-I but reduced that of C-II, consequently OCR was reduced. SMTC increased both C-I and C-II activities with PC, resulted in OCR enhancement in the mitochondria. Notably, SMTC increased OCR only with rotenone, suggesting that nNOS modulates C-II-mediated OCR in HTN. nNOSderived NO was partially reduced by malonate + PA. Taken together, nNOS attenuates C-I-mediated mitochondrial OCR in the presence of fatty acid in sham and C-I modulates nNOS activity. In HTN, nNOS attenuates C-I and C-II activities whereas interactions between nNOS and C-II maintain mitochondrial activity. Keywords nNOS . Heart . Mitochondria . Complex I . Hypertension
Introduction Fatty acids are the predominant metabolic substrates that play important roles in cardiac myocardium [11, 19] and palmitic acid (PA) is one of the common saturated fatty acids that are involved in myocardial ATP production. In the heart, nitric oxide (NO) is an essential element in regulating cardiac
* Yin Hua Zhang [email protected]
functions, including cardiac contractility, Ca2+ handling, oxidative stress, and cardiac metabolism [17]. NO regulation of mitochondrial function has been implicated to be one of the major influences of cardiac metabolism in healthy and diseased hearts [8]; however, the mechanisms remain unclear. In previous study, we have shown that neuronal nitric oxide synthase (nNOS)–derived NO exerts different functions with
4
School of Electrical Engineering and Computing, University of Newcastle, Singapore, Singapore
5
Department of Cardiac Surgery, Shanghai Institute of Cardiovas
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