Mitochondrial ATP production dynamically adapts to cellular energy demands, with calcium (Ca2+) playing a crucial regulatory role. In this review, we critically evaluate the evidence for intramitochondrial Ca2+ ([Ca2+]m) sensitivity in key energy metabolic pathways, highlighting the [Ca2+]m dependence of specific mitochondrial systems. We also address the metabolic consequences of [Ca2+]m-sensitive ATP production, particularly its effects on the utilization of specific macronutrients that fuel ATP production. Next, we discuss the primary Ca2+ entry pathway into the matrix, the mitochondrial Ca2+ uniporter (MCU), its macromolecular complex structure (MCUcx), and allosteric regulation by Ca2+. Key to this regulation are specific auxiliary subunits, along with the influence of mitochondrial inner membrane architecture. While the Ca2+ signaling plays an important role, it does not fully explain the scope for regulating ATP production. Emerging evidence suggests that additional signaling systems operating alongside the Ca2+ signaling contribute to the control of mitochondrial ATP production, a topic requiring further investigation.