Control of mitochondrial ATP synthesis in the heart

Abstract

The maintenance of a constant ATP level ('set-point') is a vital homeostatic function shared by eukaryotic cells. In particular, mammalian myocardium exquisitely safeguards its ATP set-point despite 10-fold fluctuations in cardiac workload. However, the exact mechanisms underlying this regulation of ATP homeostasis remain elusive. Here we show mitochondrial flashes (mitoflashes), recently discovered dynamic activity of mitochondria, play an essential role for the auto-regulation of ATP set-point in the heart. Specifically, mitoflashes negatively regulate ATP production in isolated respiring mitochondria and, their activity waxes and wanes to counteract the ATP supply-demand imbalance caused by superfluous substrate and altered workload in cardiomyocytes. Moreover, manipulating mitoflash activity is sufficient to inversely shift the otherwise stable ATP set-point. Mechanistically, the Bcl-xL-regulated proton leakage through F 1 F o-ATP synthase appears to mediate the coupling between mitoflash production and ATP set-point regulation. These findings indicate mitoflashes appear to constitute a digital auto-regulator for ATP homeostasis in the heart.

Mitochondrial ATP synthase F1‐β‐subunit is a calcium‐binding protein

“…Additionally, mitochondria are thought to buffer elevations of cytosolic calcium during both normal calcium signalling events and atypical calcium burdens (e.g. associated with biomineralization, disease and cell injury) [1-41. Changes in cytosolic free calcium concentration are relayed to the mitochondrial matrix, enabling mitochondrial ATP production to respond to the varying ATP demands of intracellular calcium homeostasis [2,[5][6][7]. Consistent with this scenario, several components of the ATP-producing machinery appear to be calcium-regulated.…”

“…High affinity (EF hand) calcium-binding sites were identified in this protein recently [8]. ATP synthase (F1Fo-ATPase or H+-ATPase [9,10]), also situated in the mitochondrial inner membrane, appears sensitive to physiological levels of calcium [2,6,7,11]. One proposed mechanism involves a mitochondrial 6.5 kDa inhibitor protein, termed CaBI, that binds calcium with micromolar affinity and reversibly inhibits ATP synthase in a calcium-dependent manner in vitro [12,13].…”

Excitation-contraction coupling and mitochondrial energetics

“…The main cellular energy consumers are the myosin ATPase of the contractile filaments, the plasmalemmal Na + /K + -ATPase, and the SR Ca 2+ -ATPase [15]. It is assumed that ∼2% of the cellular ATP pool is consumed in each heart beat, and during maximal workload, the whole ATP pool is turned over within a couple of seconds [7,80,139]. The main sites of energy production are the mitochondria, which take up ∼30% of cellular volume [15,222] and are located in close vicinity to the main sites of energy consumption, i. e., the myofilaments, the SR and t-tubules (Figs.…”

Does calmitine, a protein specific for the mitochondrial matrix of skeletal muscle, play a key role in mitochondrial function?

“…The fact that it has recently been localized more specifically in the mitochondrial matrix [2] suggests that it plays a primordial role in the regulation of mitochondrial bound and free calcium [3] and thus in the cellular functioning and particularly the synthesis of ATE There is increasing evidence that mitochondrial calcium, which influences the activity of various matrical enzymes involved in oxidative phosphorylation and the production of cellular energy, plays a second messenger role triggering mitochondrial response to cytosolic signals [4]. For example, at the time of muscle contraction, when the need for ATP is very great, the concentration of cytosolic calcium (released by sarcoplasmic reticulum) increases, producing an augmentation of mitochondrial calcium serving to stimulate the activity of certain matrical enzymes (dehydrogenases [5 7], ATP synthase [8]) responsible for ATP production. It is noteworthy that calcium is the only known second messenger capable of entering mitochondria.…”