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Functional interactions between complex I and complex II with nNOS in regulating cardiac mitochondrial activity in sham and hypertensive rat hearts

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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. nNOS-derived 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.

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Funding

This work was financially supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019R1A2C1005720), National Natural Science Foundation of China (NSFC 31660284, NSFC31860288) and Seoul National University Research Grant 2018.

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Authors and Affiliations

  1. Yanbian University Hospital, Yanji, 133000, Jilin Province, China

    Yu Na Wu & Yin Hua Zhang

  2. Department of Physiology & Biomedical Sciences, Ischemic/Hypoxic Disease Institutes, Seoul National University, College of Medicine, Jongno-Gu, Seoul, Republic of Korea

    Yu Na Wu, Sung Joon Kim & Yin Hua Zhang

  3. Biomedical Engineering, School of Science and Technology, Singapore University of Social Sciences, Singapore, Singapore

    Vidya K Sudarshan

  4. School of Electrical Engineering and Computing, University of Newcastle, Singapore, Singapore

    Vidya K Sudarshan

  5. Department of Cardiac Surgery, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

    Shi Chao Zhu

  6. Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China, Fudan University, Shanghai, China

    Yong Feng Shao

  7. Institute of Cardiovascular Sciences, Faculty of Biology, Medicine and Health Sciences, University of Manchester, Manchester, UK

    Yin Hua Zhang

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  1. Yu Na Wu
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Wu, Y.N., Sudarshan, V.K., Zhu, S.C. et al. Functional interactions between complex I and complex II with nNOS in regulating cardiac mitochondrial activity in sham and hypertensive rat hearts. Pflugers Arch - Eur J Physiol 472, 1743–1755 (2020). https://doi.org/10.1007/s00424-020-02458-2

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