In heart failure, alterations of Na ⁺ and Ca ²⁺ handling, energetic deficit, and oxidative stress in cardiac myocytes are important pathophysiological hallmarks. Mitochondria are central to these processes because they are the main source for ATP, but also reactive oxygen species (ROS), and their function is critically controlled by Ca ²⁺ . During physiological variations of workload, mitochondrial Ca ²⁺ uptake is required to match energy supply to demand but also to keep the antioxidative capacity in a reduced state to prevent excessive emission of ROS. Mitochondria take up Ca ²⁺ via the mitochondrial Ca ²⁺ uniporter, which exists in a multiprotein complex whose molecular components were identified only recently. In heart failure, deterioration of cytosolic Ca ²⁺ and Na ⁺ handling hampers mitochondrial Ca ²⁺ uptake and the ensuing Krebs cycle–induced regeneration of the reduced forms of NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate), giving rise to energetic deficit and oxidative stress. ROS emission from mitochondria can trigger further ROS release from neighboring mitochondria termed ROS-induced ROS release, and cross talk between different ROS sources provides a spatially confined cellular network of redox signaling. Although low levels of ROS may serve physiological roles, higher levels interfere with excitation–contraction coupling, induce maladaptive cardiac remodeling through redox-sensitive kinases, and cell death through mitochondrial permeability transition. Targeting the dysregulated interplay between excitation–contraction coupling and mitochondrial energetics may ameliorate the progression of heart failure.

Rationale:: Mitochondrial Ca ²⁺ uptake is essential for the bioenergetic feedback response through stimulation of Krebs cycle dehydrogenases. Close association of mitochondria to the sarcoplasmic reticulum (SR) may explain efficient mitochondrial Ca ²⁺ uptake despite low Ca ²⁺ affinity of the mitochondrial Ca ²⁺ uniporter. However, the existence of such mitochondrial Ca ²⁺ microdomains and their functional role are presently unresolved. Mitofusin (Mfn) 1 and 2 mediate mitochondrial outer membrane fusion, whereas Mfn2 but not Mfn1 tethers endoplasmic reticulum to mitochondria in noncardiac cells. Objective:: To elucidate roles for Mfn1 and 2 in SR-mitochondrial tethering, Ca ²⁺ signaling, and bioenergetic regulation in cardiac myocytes. Methods and Results:: Fruit fly heart tubes deficient of the Drosophila Mfn ortholog MARF had increased contraction-associated and caffeine-sensitive Ca ²⁺ release, suggesting a role for Mfn in SR Ca ²⁺ handling. Whereas cardiac-specific Mfn1 ablation had no effects on murine heart function or Ca ²⁺ cycling, Mfn2 deficiency decreased cardiomyocyte SR-mitochondrial contact length by 30% and reduced the content of SR-associated proteins in mitochondria-associated membranes. This was associated with decreased mitochondrial Ca ²⁺ uptake (despite unchanged mitochondrial membrane potential) but increased steady-state and caffeine-induced SR Ca ²⁺ release. Accordingly, Ca ²⁺ -induced stimulation of Krebs cycle dehydrogenases during β-adrenergic stimulation was hampered in Mfn2-KO but not Mfn1-KO myocytes, evidenced by oxidation of the redox states of NAD(P)H/NAD(P) ⁺ and FADH ₂ /FAD. Conclusions:: Physical tethering of SR and mitochondria via Mfn2 is essential for normal interorganelle Ca ²⁺ signaling in the myocardium, consistent with a requirement for SR-mitochondrial Ca ²⁺ signaling through microdomains in the cardiomyocyte bioenergetic feedback response to physiological stress.

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca²⁺. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation–contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.