Received: 7 August 2018 | Accepted: 22 October 2018 DOI: 10.1002/jcp.27754 REVIEW ARTICLE Mitochondrial dysfunction in diabetes and the regulatory roles of antidiabetic agents on the mitochondrial function Habib Yaribeygi 1 | Stephen L. Atkin 2 | Amirhossein Sahebkar 3,4,5 1 Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2 Weill Cornell Medicine Qatar, Doha, Qatar 3 Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 4 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran 5 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Correspondence Amirhossein Sahebkar, PharmD, PhD, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, P.O. Box 91779‐48564, Mashhad, Iran. Email: sahebkara@mums.ac.ir; amir_saheb2000@yahoo.com Habib Yaribeygi, Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Email: habib.yari@yahoo.com Abstract The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly with its associated morbidity and mortality. Many pathophysiological pathways such as oxidative stress, inflammatory responses, adipokines, obesity‐induced insulin resis- tance, improper insulin signaling, and beta cell apoptosis are associated with the development of T2DM. There is increasing evidence of the role of mitochondrial dysfunction in the onset of T2DM, particularly in relation to the development of diabetic complications. Here, the role of mitochondrial dysfunction in T2DM is reviewed together with its modulation by antidiabetic therapeutic agents, an effect that may be independent of their hypoglycemic effect. KEYWORDS antidiabetic agents, diabetic complications, diabetes mellitus, mitochondria, mitochondrial dysfunction 1 | INTRODUCTION Type 2 diabetes mellitus (T2DM) is the most prevalent metabolic disorder globally (Semenkovich, Brown, Svrakic, & Lustman, 2015; Zimmet, Alberti, Magliano, & Bennett, 2016) with a widespread impact on differing tissues and their underlying cellular processes (Asmat, Abad, & Ismail, 2016; Levy, Gavin, & Sowers, 1994). Poor diabetes control is associated with considerable morbidity and tissue injury (Yaribeygi, Farrokhi, Rezaee, & Sahebkar, 2018a). T2DM affects functioning of the nucleus (Chen et al., 2017), sarcoplasmic reticulum (Dhalla, Rangi, Zieroth, & Xu, 2012), Golgi apparatus (Weiss, 2013), and the cell membrane (Holmes, 2016; Weijers, 2012) with damage to these organelles leading to diabetic complications (Brownlee, 2001; Rahimi, Nikfar, Larijani, & Abdollahi, 2005; Vincent, Callaghan, Smith, & Feldman, 2011). Mitochondrial dysfunction may be caused by a number of mechanisms such as mitochondrial DNA (mtDNA) mutation, mitochon- drial swelling, disrupted electron potential across the mitochondrial inner membrane, and mitochondrial oxidative stress (Lowell & Shulman, 2005). Because most eukaryotic cells have mitochondria, their dysfunc- tion affecting cellular respiration and pathways of energy production will affect many tissues and contribute to the development of diabetic complications (DiMauro & Schon, 2003). The first goal in the diabetes treatment is the optimization of glycemic control and if these therapeutic agents have protective effects on mitochondria indepen- dent of their hypoglycemic effects, then this would be beneficial. Therefore, in this review, we focus on the most recent findings regarding mitochondrial protective effects of these antidiabetic agents. 2 | PHYSIOLOGY OF MITOCHONDRIA Mitochondria are double‐membrane cellular respiratory organelles that are important for energy production (adenosine triphosphate [ATP] production) via aerobic respiration of cells, calcium storage, J Cell Physiol. 2018;1-9. wileyonlinelibrary.com/journal/jcp © 2018 Wiley Periodicals, Inc. | 1