Regulation of mitochondrial oxidative phosphorylation through tight control of cytochrome c oxidase in health and disease – Implications for ischemia/reperfusion injury, inflammatory diseases, diabetes, and cancer

Mitochondria are essential to cellular function as they generate the majority of cellular ATP, mediated through oxidative phosphorylation, which couples proton pumping of the electron transport chain (ETC) to ATP production. The ETC generates an electrochemical gradient, known as the proton motive force, consisting of the mitochondrial membrane potential (ΔΨ m , the major component in mammals) and ΔpH across the inner mitochondrial membrane. Both ATP production and reactive oxygen species (ROS) are linked to ΔΨ m , and it has been shown that an imbalance in ΔΨ m beyond the physiological optimal intermediate range results in excessive ROS production. The reaction of cytochrome c oxidase (COX) of the ETC with its small electron donor cytochrome c (Cyt c ) is the proposed rate-limiting step in mammals under physiological conditions. The rate at which this redox reaction occurs controls ΔΨ m and thus ATP and ROS production. Multiple mechanisms are in place that regulate this reaction to meet the cell’s energy demand and respond to acute stress. COX and Cyt c have been shown to be regulated by all three main mechanisms, which we discuss in detail: allosteric regulation, tissue-specific isoforms, and post-translational modifications for which we provide a comprehensive catalog and discussion of their functional role with 55 and 50 identified phosphorylation and acetylation sites on COX, respectively. Disruption of these regulatory mechanisms has been found in several common human diseases, including stroke and myocardial infarction, inflammation including sepsis, and diabetes, where changes in COX or Cyt c phosphorylation lead to mitochondrial dysfunction contributing to disease pathophysiology. Identification and subsequent targeting of the underlying signaling pathways holds clear promise for future interventions to improve human health. An example intervention is the recently discovered noninvasive COX-inhibitory infrared light therapy that holds promise to transform the current standard of clinical care in disease conditions where COX regulation has gone awry. Graphical abstract summarizing the major regulatory mechanisms of Cytochrome c oxidase. • Post-translational modifications such as phosphorylations on cytochrome c oxidase (COX) and cytochrome c modulate enzymatic function and control oxidative phosphorylation and reactive oxygen species production. • Loss or changes of regulatory post-translational modifications of COX are implicated in various human diseases, such as ischemia/reperfusion injury following myocardial infarction and stroke. • Targeting and restoring regulation and physiological function to COX is a sensible therapeutic target, either directly through infrared light immediately altering COX activity when applied or indirect mechanisms such as targeting signaling pathway. • With current-day mass spectrometry methods, researchers can now identify and quantify modified proteins, measure the fraction of modified proteins, and provide biological context to identify those posttranslational modifications that are physiologically relevant.