The mitochondrial calcium uniporter (MCU) is a multicomponent channel that is the primary mechanism for mitochondrial Ca
2+
uptake (
m
Ca
2+
). We previously reported that the MCU is required for energetic signaling to meet contractile demand during the ‘fight or flight’ response. In addition, we showed that deletion of the pore-forming component (
Mcu
gene) protected against mitochondria permeability transition pore (MPTP) opening and ischemia-reperfusion injury. However, results from our study and others questioned the physiological relevance of MCU-mediated Ca
2+
uptake during chronic stress states featuring sustained intracellular Ca
2+
load (
i
Ca
2+
). To address this, we deleted
Mcu
from cardiomyocytes in adult mice (
Mcu
cKO) and implanted osmotic pumps to deliver the β adrenergic agonist isoproterenol (iso, 70 mg/kg/day for 14d). In contrast to controls,
Mcu
cKO mice lacked contractile responsiveness to chronic βAR stimulation with evidence of LV dysfunction and failure by d14 (
Fig 1
). Next, we crossed the
Mcu
cKO with mice overexpressing the β2a subunit (β2a-Tg) of the L-type Ca
2+
channel (LTCC). This model displays enhanced LTCC activity and cardiac contractility, but with added stress such as iso infusion, Ca
2+
overload eventually leads to MPTP-dependent cell death and heart failure. Surprisingly, loss of
Mcu
in this model was lethal with all mice dying by d13 (
Fig 2
). Baseline echocardiography revealed that loss of
Mcu
ablated all β2a-mediated enhancements in LV contractility and accelerated dysfunction post-iso. These findings demonstrate that MCU-mediated
m
Ca
2+
uptake is critical to meet energetic demand during chronic stress states featuring sustained
i
Ca
2+
load.
Cyclophilin D-mediated regulation of the permeability transition pore is altered in mice lacking the mitochondrial calcium uniporter
