Already in the early 1960s, researchers noted the potential of mitochondria to take up large amounts of Ca2+. However, the physiological role and the molecular identity of the mitochondrial Ca2+ uptake mechanisms remained elusive for a long time. The identification of the individual components of the mitochondrial calcium uniporter complex (MCUC) in the inner mitochondrial membrane in 2011 started a new era of research on mitochondrial Ca2+ uptake. Today, many studies investigate mitochondrial Ca2+ uptake with a strong focus on function, regulation, and localization of the MCUC. However, on its way into mitochondria Ca2+ has to pass two membranes, and the first barrier before even reaching the MCUC is the outer mitochondrial membrane (OMM). The common opinion is that the OMM is freely permeable to Ca2+. This idea is supported by the presence of a high density of voltage-dependent anion channels (VDACs) in the OMM, forming large Ca2+ permeable pores. However, several reports challenge this idea and describe VDAC as a regulated Ca2+ channel. In line with this idea is the notion that its Ca2+ selectivity depends on the open state of the channel, and its gating behavior can be modified by interaction with partner proteins, metabolites, or small synthetic molecules. Furthermore, mitochondrial Ca2+ uptake is controlled by the localization of VDAC through scaffolding proteins, which anchor VDAC to ER/SR calcium release channels. This review will discuss the possibility that VDAC serves as a physiological regulator of mitochondrial Ca2+ uptake in the OMM.

Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this unique role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.

We studied the effects of norepinephrine on 42K turnover in aorta isolated from rats. The rats were given saline to drink and were made hypertensive by injections of deoxycorticosterone acetate (DOC). Other groups of rats received in addition either 6-hydroxydopamine (6-OH-DA) or a regimen of antihypertensives (Anti-Hy) consisting of reserpine, hydrochlorothiazide, and hydralazine. The weight, length, wall thickness, and circumference of the aorta also were measured. DOC hypertension was associated with increased 42K turnover (rate constant for DOC = 0.0164 +/- 0.0009 vs. 0.0090 +/- 0.0002 min-1 in controls). The responses of 42K turnover to low doses of norepinephrine (NE) were increased in DOC with an ED50 of 3.5 +/- 0.8 X 10(-9) vs. 2.7 +/- 0.5 X 10(-8) M in controls. The aortic weight, weight/length, and wall thickness were also increased. Rats treated with DOC plus 6-OH-DA had lower blood pressure and smaller changes in aortic dimensions; however 42K turnover and response to NE were similar to those of the DOC group. The Anti-Hv group exhibited only small increase in 42K turnover and aortic dimensions when compared to controls. It is concluded that DOC hypertension is associated with increased response of 42K turnover to NE which in turn may contribute to increased responses reported for contraction. The Anti-Hy regimen was more effective than 6-OH-DA in reducing the increased 42K turnover and response to NE associated with DOC hypertension.

Ethics approval statementAll human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Intracellular calcium mediates the bidirectional coupling between excitation and contraction (ECC) in cardiac myocytes, whereby calcium affects electrophysiology and vice versa. Abnormalities in ECC can precipitate