We have read with interest the recently published Perspective by Kumar Sharma (1) and write to express our views. The author presents a controversial viewpoint, which clearly challenges the mitochondrial superoxide theory proposed by Michael Brownlee in 2001 (2). Thus, it is proposed that there may be reduced, rather than increased, mitochondrial superoxide production due to compromised electron transport chain (ETC) function in diabetes. While a significant recent literature is cited to refute the Brownlee hypothesis, several recent reports showing the involvement of mitochondrial superoxide generation and diabetes complications warrant consideration (3,4).
The pathophysiology of diabetes complications should be envisioned as a series of dynamic and interrelated changes occurring over a period of time, and hence, alterations at one particular time point cannot provide context as to the overall processes driving the development and progression of disease. Hyperglycemia is known to produce initial NADH flux–mediated reductive stress followed by oxidative stress in diabetes (5). Thus, hyperglycemia may well initially enhance mitochondrial ETC flux and increase superoxide generation as suggested by Brownlee (2). And the enhanced free radicals can via mitochondrial damage either directly attack the ETC complex or cause mutations in naked mitochondrial DNA (6,7). Hence at this stage, ETC functioning may be reduced, resulting in reduced superoxide generation. Hyperglycemia may also mediate reduced mitochondrial superoxide production due to a maladaptive cellular feedback response to initial mitochondrial reactive oxygen species (ROS) generation (8). Uncoupling protein response by hydroxynonenal formation and poly(ADP-ribosyl)ation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by poly(ADP-ribose) polymerase (PARP) activation in response to mitochondrial ROS generation leads to reduced mitochondrial membrane potential and electron shuttling through the ETC complex and less ROS leakage (9,10).
Adenosine monophosphate kinase (AMPK) maintains mitochondrial integrity and replaces damaged, dysfunctional mitochondria through peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) activation and mitophagy stimulation, respectively (11). PGC-1α boosts mitochondrial DNA replication and transcription via activation of mitochondrial transcription factor A (mtTFA) and nuclear respiratory factor 1 (NRF1) (12). Several studies have also shown that activation of AMPK in diabetic and nondiabetic animal models results in reduced mitochondrial ROS production in contrast to the feed-forward hypothesis (13). Increased mitochondrial ROS production and reduced AMPK activity in the hyperglycemic state was recently demonstrated by Nishikawa et al. (14). Accordingly, enhanced mitochondrial ROS in hyperglycemia damages DNA and activates PARP, leading to reduced NAD+ concentration and function of the NAD+-dependent protein deacetylase sirtuin 1 (SIRT1) (14). The malfunction of SIRT1 results in diminished deacetylation and inactivation of liver kinase B (LKB1), the upstream activator of AMPK (15).
Thus, given that the pharmacological stimulation of AMPK and PGC-1α can augment mitochondrial biogenesis and functional capacity in diabetes (11,13), there will be considerable therapeutic interest in this area over the coming years.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
