N-Acetyl cysteine ameliorates hyperglycemia-induced cardiomyocyte toxicity by improving mitochondrial energetics and enhancing endogenous Coenzyme Q9/10 levels

Phiwayinkosi V Dludla; Patrick Orlando; Sonia Silvestri; Sithandiwe E Mazibuko-Mbeje; Rabia Johnson; Fabio Marcheggiani; Ilenia Cirilli; Christo J F Muller; Johan Louw; Nnini Obonye; Thembeka Nyawo; Bongani B Nkambule; Luca Tiano

doi:10.1016/j.toxrep.2019.11.004

N-Acetyl cysteine ameliorates hyperglycemia-induced cardiomyocyte toxicity by improving mitochondrial energetics and enhancing endogenous Coenzyme Q_9/10 levels

Toxicol Rep. 2019 Nov 5:6:1240-1245. doi: 10.1016/j.toxrep.2019.11.004. eCollection 2019.

Authors

Phiwayinkosi V Dludla^{1

2}, Patrick Orlando², Sonia Silvestri², Sithandiwe E Mazibuko-Mbeje^{1

3}, Rabia Johnson^{1

3}, Fabio Marcheggiani², Ilenia Cirilli², Christo J F Muller^{1

3

4}, Johan Louw^{1

4}, Nnini Obonye^{1

3}, Thembeka Nyawo^{1

3}, Bongani B Nkambule⁵, Luca Tiano²

Affiliations

¹ Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa.
² Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona 60131, Italy.
³ Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa.
⁴ Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa.
⁵ School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa.

Abstract

The diabetic heart has been linked with reduced endogenous levels of coenzyme Q_9/10 (CoQ), an important antioxidant and component of the electron transport chain. Although CoQ has displayed cardioprotective potential in experimental models of diabetes, the impact of N-acetyl cysteine (NAC) on mitochondrial energetics and endogenous levels of CoQ remains to be clarified. To explore these effects, high glucose-exposed H9c2 cardiomyocytes were used as an experimental model of hyperglycemia-induced cardiac injury. The results showed that high glucose exposure caused an increased production of reactive oxygen species (ROS), which was associated with impaired mitochondrial energetics as confirmed by a reduction of maximal respiration rate and depleted ATP levels. These detrimental effects were consistent with significantly reduced endogenous CoQ levels and accelerated cell toxicity. Although metformin demonstrated similar effects on mitochondrial energetics and cell viability, NAC demonstrated a more pronounced effect in ameliorating cytosolic and mitochondrial ROS production. Interestingly, the ameliorative effects of NAC against hyperglycemia-induced injury were linked with its capability to enhance endogenous CoQ levels. Although such data are to be confirmed in other models, especially in vivo studies, the overall findings provide additional evidence on the therapeutic mechanisms by which NAC protects against diabetes-induced cardiac injury.

Keywords: ATP, adenosine triphosphate; CoQ9/10, Coenzyme Q9/10; Coenzyme Q; DCFH-DA, dichlorofluorescein diacetate; DMEM, Dulbecco’s Modified Eagle’s Medium; Diabetes; ECAR, extracellular acidification rates; FBS, fetal bovine serum; HPLC, high-performance liquid chromatograph; Hyperglycemia; MET, metformin; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Mitochondrial energetics; N-Acetyl cysteine; NAC, N-acetyl cysteine; PBS, Phosphate buffered saline; ROS, reactive oxygen species; Reactive oxygen species.