Cytoprotection by the modulation of mitochondrial electron transport chain: the emerging role of mitochondrial STAT3

Abstract

The down regulation of mitochondrial electron transport is an emerging mechanism of cytoprotective intervention that is effective in pathologic settings such as myocardial ischemia and reperfusion when the continuation of mitochondrial respiration produces reactive oxygen species, mitochondrial calcium overload, and the release of cytochrome c to activate cell death programs. The initial target of deranged electron transport is the mitochondria themselves. In the first part of this review, we describe this concept and summarize different approaches used to regulate mitochondrial respiration by targeting complex I as a proximal site in the electron transport chain (ETC) in order to favor the cytoprotection. The second part of the review highlights the emerging role of signal transducer and activator of transcription 3 (STAT3) in the direct, non-transcriptional regulation of ETC, as an example of a genetic approach to modulate respiration. Recent studies indicate that a pool of STAT3 resides in the mitochondria where it is necessary for the maximal activity of complexes I and II of the electron transport chain (ETC). The overexpression of mitochondrial-targeted STAT3 results in a partial blockade of electron transport at complexes I and II that does not impair mitochondrial membrane potential nor enhance the production of reactive oxygen species (ROS). The targeting of transcriptionally-inactive STAT3 to mitochondria attenuates damage to mitochondria during cell stress, resulting in decreased production of ROS and retention of cytochrome c by mitochondria. The overexpression of STAT3 targeted to mitochondria unveils a novel protective approach mediated by modulation of mitochondrial respiration that is independent of STAT3 transcriptional activity. The limitation of mitochondrial respiration under pathologic circumstances can be approached by activation and overexpression of endogenous signaling mechanisms in addition to pharmacologic means. The regulation of mitochondrial respiration comprises a cardioprotective paradigm to decrease cellular injury during ischemia and reperfusion.

Figure 1. STAT3 expression in heart mitochondria affects mitochondrial function

(A) Cardiac-specific deletion of STAT3 results in a 50% decrease in complex I activity (Wegrzyn et al., 2009), whereas mitochondria-targeted over expression of STAT3 (MLS-STAT3E) leads to a modest 20% reduction in complex I activity (Szczepanek et al., 2011). Results are means ± SEM, n=4 for both groups. (B) Over expression of mitochondria-targeted, transcriptionally inactive STAT3 (MLS-STAT3E) decreases ROS production and blocks cytochrome c release during ischemia (Szczepanek et al., 2011). Results are means ± SEM, n=4 for both groups. Y axis depicts the ischemia-induced increase in net release of H₂O₂ from mitochondria respiring with glutamate+malate as complex I substrate, expressed as percent increase compared to time control (mitochondria from non-ischemic hearts). X axis depicts cytochrome c release and is shown as a percent decrease in signal compared to cytochrome c in time control samples.

Figure 2. Postulated mechanism of the protective role of STAT3 in heart mitochondria during ischemia

(A) In wild type mitochondria ischemia increases superoxide production from complex I that is directed toward the matrix. This results in cardiolipin oxidation and cytochrome c delocalization from the inner membrane. Further damage to the mitochondria leads to outer membrane permeabilization, which allows the release of cytochrome c from mitochondria and the subsequent induction of apoptosis. (B) Over expression of MLS-STAT3E in the mitochondria partially blocks electron flow through iron-sulfur clusters within complex I, resulting in blockade of superoxide generation from complex I during ischemia. This in turn decreases cardiolipin oxidation and preserves cytochrome c retention in the inner membrane. Less ROS and the lack of cytochrome c translocation into the cytosol attenuates apoptosis and increases cell viability during oxidative stress. STAT3, signal transducer and activator of transcription 3; C-I, II, III and IV, respiratory complex I, II, III and IV; cyt c, cytochrome c; Q, ubiquinone; FMN, flavin mononucleotide; Fe-S, iron-sulfur cluster; NADH, nicotinamide adenine dinucleotide; ISCH, ischemia; ROS, reactive oxygen species; MnSOD, mitochondrial manganese superoxide dismutase; CL, cardiolipin; CL^ox, oxidized cardiolipin; MOMP, mitochondrial outer membrane permeabilization.