Abstract
The survival of a cell depends on its ability to meet its energy requirements. We hypothesized that the mitochondrial reserve respiratory capacity (RRC) of a cell is a critical component of its bioenergetics that can be utilized during an increase in energy demand, thereby, enhancing viability. Our goal was to identify the elements that regulate and contribute to the development of RRC and its involvement in cell survival. The results show that activation of metabolic sensors, including pyruvate dehydrogenase and AMP-dependent kinase, increases cardiac myocyte RRC via a Sirt3-dependent mechanism. Notably, we identified mitochondrial complex II (cII) as a target of these metabolic sensors and the main source of RRC. Moreover, we show that RRC, via cII, correlates with enhanced cell survival after hypoxia. Thus, for the first time, we show that metabolic sensors via Sirt3 maximize the cellular RRC through activating cII, which enhances cell survival after hypoxia.
Highlights
One potential source of respiratory capacity (RRC) is a regulated increase of substrate entry into the TCA cycle that is synchronized with an increase in the electron transport chain (ETC) activity
AICAR enhanced extracellular acidification rates (ECAR), indicating an increase in glycolysis (Figures 4b and c, lower panels). These results indicate that activation of pyruvate dehydrogenase in either neonatal cardiac myocytes or hiPSC-CM has the capacity to significantly increase RRC and, thereby, restore the cells’ bioenergetics after exposure to hypoxia
We show that cardiac myocytes operate on a fraction of their mitochondrial respiratory capacity under conditions where the preferred metabolic substrates are available
Summary
One potential source of RRC is a regulated increase of substrate entry into the TCA cycle that is synchronized with an increase in the electron transport chain (ETC) activity. Mammalian complex II (cII) has the unique characteristic of being a common component that links the TCA cycle and the ETC and its role in cell survival and death is well established. We show that holo-cII is the source of the RRC, which increases the cells’ resistant to cell death
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