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Altered levels of intracellular calcium (Ca2+) are a highly prevalent feature in different forms of cardiac injury, producing changes in contractility, arrhythmias, and mitochondrial dysfunction. In cardiac ischemia-reperfusion injury, mitochondrial Ca2+ overload leads to pathological production of reactive oxygen species (ROS), activates the permeability transition, and cardiomyocyte death. Here we investigated the cardiac phenotype caused by deletion of EF-hand domain-containing protein D1 (Efhd1 −/−), a Ca2+-binding mitochondrial protein whose function is poorly understood. Efhd1 −/− mice are viable and have no adverse cardiac phenotypes. They feature reductions in basal ROS levels and mitoflash events, both important precursors for mitochondrial injury, though cardiac mitochondria have normal susceptibility to Ca2+ overload. Notably, we also find that Efhd1 −/− mice and their cardiomyocytes are resistant to hypoxic injury. [Display omitted] • EFHD1 localizes to the mitochondrial outer membrane and intermembrane space. • Efhd1 −/− mice exhibit normal cardiac function. • Efhd1 −/− mice have reduced mitochondrial Ca2+, ΔΨ, ROS, and mitoflash levels. • Efhd1 −/− mouse cardiomyocytes are resistant to ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Recently reported kinase-linked mild depolarization of mitochondria, which prevents the generation of the reactive oxygen species (ROS) and disappears in various organs of the old mice, has been assumed to represent a crucial component of the mitochondrial anti-aging program. To measure mitochondrial inner membrane potential (IMP), the authors used fluorescent probe safranin O+. It is widely accepted that the accumulation of such cationic probes in the mitochondrial matrix depends exclusively on IMP, thus completely ignoring the possibility of the outer membrane potential (OMP) generation. However, computational analysis performed in the presented work suggests that the kinase-linked generation of the positive OMP might take place under the described conditions, because the measured potential includes the algebraic sum of both IMP and OMP. Alternatively to the suggested mild depolarization of mitochondria, the reported experimental data might reflect mainly a change of the positive OMP generated by the VDAC-kinase complexes. We also demonstrate that the reported in the literature mitochondrial hyperpolarization induced by erastin (known to prevent VDAC-tubulin interactions) and the depolarization caused by the mitochondrial VDAC knockdowns in the cancer cells might actually represent a decrease or increase, respectively, of the magnitude of the kinase-linked positive OMP. This is consistent with our hypothesis that VDAC voltage gating by the kinase-linked metabolically-dependent OMP plays a very important physiological role in regulating the cell energy metabolism under normal and pathological conditions, in the maintenance of the cell death resistance and even in the genetic aging program. [Display omitted] • Kinase-linked generation of the positive outer membrane potential in mitochondria • Alternative explanations of an apparent hyperpolarization-depolarization of mitochondria • VDAC knockdowns increase kinase-linked outer membrane potential in mitochondria. • Role of the positive outer membrane potential of mitochondria in cell death protection • Possible aging program at the level of the mitochondrial outer membrane [ABSTRACT FROM AUTHOR]