Regulation of Mitochondrial ATP Production: Ca²⁺ Signaling and Quality Control

Cardiac ATP production primarily depends on oxidative phosphorylation in mitochondria and is dynamically regulated by Ca²⁺ levels in the mitochondrial matrix as well as by cytosolic ADP. We discuss mitochondrial Ca²⁺ signaling and its dysfunction which has recently been linked to cardiac pathologies including arrhythmia and heart failure. Similar dysfunction in other excitable and long-lived cells including neurons is associated with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Central to this new understanding is crucial Ca²⁺ regulation of both mitochondrial quality control and ATP production. Mitochondria-associated membrane (MAM) signaling from the sarcoplasmic reticulum (SR) and the endoplasmic reticulum (ER) to mitochondria is discussed. We propose future research directions that emphasize a need to define quantitatively the physiological roles of MAMs, as well as mitochondrial quality control and ATP production.