Mitochondrial Ca and Energetics

Mitochondrial Ca and energetics are interrelated via several Ca-dependent dehydro­genases, which raise NADH production and thus ATP production when mitochondrial [Ca] ([Ca]m) is increased. Our critical studies demonstrated the dynamics of this [Ca]m-dependent NADH regulation in intact myocardium, where work-loads due to increased [Ca]i cause feed-forward energetic activation, while Ca-independent (Starling Law) workloads do not. We also resolved controversy about the magnitude and kinetics of [Ca]m changes during the cardiac cycle and heart rate changes.  Individual [Ca]m transients at each heartbeat are quite small, and decline slowly, causing [Ca]m to be a slow integrating regulatory system to better match ATP supply with demand. We also showed how the mitochondrial Ca uniporter (MCU) is essential in mediating rapid mitochondrial, that an endogenous homolog MCUb serves as an inhibitory subunit in the MCU complex and that rare transient permeability transition pore (PTP) openings may serve a protective role, preventing mitochondrial death by permanent PTP opening.

 

1. Brandes R, Bers DM: Intracellular [Ca] increases the mitochondrial NADH concentration during elevated work in intact cardiac muscle.  Circ. Res. 80:82-87, 1997. 146 Citations

2. Lu X, Ginsburg KS, Kettlewell S, Bossuyt J, Smith GL, Bers DM.  Local gradients of intra-mitochondrial [Ca] in cardiac myocytes during sarcoplasmic reticulum Ca release. Circ Res. 112:424-431, 2013.

3. Kwong JQ, Lu X, Correll RN, Vagnozzi RJ, Sargent MA, York AJ, Zhang J, Bers DM, Molkentin JD. The mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart. Cell Reports. 12:15-22, 2015.

4. Lu X, Kwong J, Molkentin JD, Bers DM. Individual cardiac mitochondria undergo rare transient permeability transition pore openings. Circ Res 118:834-841, 2016.  Highlighted by Editorial.

5. Lu X, Thai PN, Lu S, Pu J, Bers DM. Intrafibrillar and perinuclear mitochondrial heterogeneity in adult cardiac myocytes. J Mol Cell Cardiol. 136:72-84, 2019.

6. Huo J, Lu S, Kwong JQ, Bround MJ, Grimes KM, Sargent MA, Brown ME, Davis ME, Bers DM, Molkentin JD. MCUb induction protects the heart from post ischemic remodeling. Circ Res. 127:379-390, 2020. Highlighted by Editorial