Mitochondrial Hormesis and Diabetic Complications

e32 Diabetes Volume 64, September 2015

Ashutosh Kumar,1 Veera Ganesh Yerra,1 and Rayaz A. Malik2

COMMENT ON SHARMA Mitochondrial Hormesis and Diabetic Complications. Diabetes 2015;64:663–672

Diabetes 2015;64:e32–e33 | DOI: 10.2337/db15-0589

We have read with interest the recently published Perspec- leads to reduced mitochondrial membrane potential and tive by Kumar Sharma (1) and write to express our views. electron shuttling through the ETC complex and less ROS The author presents a controversial viewpoint, which leakage (9,10). clearly challenges the mitochondrial superoxide theory Adenosine monophosphate kinase (AMPK) maintains proposed by Michael Brownlee in 2001 (2). Thus, it is mitochondrial integrity and replaces damaged, dysfunctional proposed that there may be reduced, rather than in- mitochondria through peroxisome proliferator–activated re- creased, mitochondrial superoxide production due to ceptor g coactivator-1a (PGC-1a) activation and mitophagy compromised electron transport chain (ETC) function in stimulation, respectively (11). PGC-1a boosts mitochondrial diabetes. While a signiﬁcant recent literature is cited to re- DNA replication and transcription via activation of mito- fute the Brownlee hypothesis, several recent reports show- chondrial transcription factor A (mtTFA) and nuclear respi- ing the involvement of mitochondrial superoxide generation ratory factor 1 (NRF1) (12). Several studies have also shown and diabetes complications warrant consideration (3,4). that activation of AMPK in diabetic and nondiabetic animal The pathophysiology of diabetes complications should models results in reduced mitochondrial ROS production in be envisioned as a series of dynamic and interrelated changes contrast to the feed-forward hypothesis (13). Increased

COMMENTS AND RESPONSES occurring over a period of time, and hence, alterations at one mitochondrial ROS production and reduced AMPK activ- – particular time point cannot provide context as to the overall ity in the hyperglycemic state was recently demonstrated processes driving the development and progression of by Nishikawa et al. (14). Accordingly, enhanced mitochon- disease. Hyperglycemia is known to produce initial NADH drial ROS in hyperglycemia damages DNA and activates 1 flux–mediated reductive stress followed by oxidative PARP, leading to reduced NAD concentration and func- 1 stress in diabetes (5). Thus, hyperglycemia may well ini- tion of the NAD -dependent protein deacetylase sirtuin 1 e-LETTERS tially enhance mitochondrial ETC flux and increase super- (SIRT1) (14). The malfunction of SIRT1 results in diminished oxide generation as suggested by Brownlee (2). And the deacetylation and inactivation of liver kinase B (LKB1), the enhanced free radicals can via mitochondrial damage ei- upstream activator of AMPK (15). ther directly attack the ETC complex or cause mutations Thus, given that the pharmacological stimulation of AMPK in naked mitochondrial DNA (6,7). Hence at this stage, and PGC-1a can augment mitochondrial biogenesis and func- ETC functioning may be reduced, resulting in reduced tional capacity in diabetes (11,13), there will be considerable superoxide generation. Hyperglycemia may also mediate therapeutic interest in this area over the coming years. reduced mitochondrial superoxide production due to a maladaptive cellular feedback response to initial mitochon- Duality of Interest. fl drial reactive oxygen species (ROS) generation (8). Uncou- No potential con icts of interest relevant to this article pling protein response by hydroxynonenal formation and were reported. poly(ADP-ribosyl)ation of glyceraldehyde-3-phosphate de- References hydrogenase (GAPDH) by poly(ADP-ribose) polymerase (PARP) 1. Sharma K. Mitochondrial hormesis and diabetic complications. Diabetes activation in response to mitochondrial ROS generation 2015;64:663–672

1Department of Pharmacology and Toxicology, National Institute of Pharmaceu- © 2015 by the American Diabetes Association. Readers may use this article as tical Education and Research Hyderabad, Hyderabad, India long as the work is properly cited, the use is educational and not for proﬁt, and 2Centre for Endocrinology and Diabetes, University of Manchester, Manchester, the work is not altered. U.K. Corresponding author: Ashutosh Kumar, [email protected]. diabetes.diabetesjournals.org Kumar, Yerra, and Malik e33

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