Affiliation:
1. From the Johns Hopkins University, Institute of Molecular Cardiobiology, Division of Cardiology, Baltimore, Md. Current address for C.M.: Universität des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany.
Abstract
Mitochondrial Ca
2+
([Ca
2+
]
m
) regulates oxidative phosphorylation and thus contributes to energy supply and demand matching in cardiac myocytes. Mitochondria take up Ca
2+
via the Ca
2+
uniporter (MCU) and extrude it through the mitochondrial Na
+
/Ca
2+
exchanger (mNCE). It is controversial whether mitochondria take up Ca
2+
rapidly, on a beat-to-beat basis, or slowly, by temporally integrating cytosolic Ca
2+
([Ca
2+
]
c
) transients. Furthermore, although mitochondrial Ca
2+
efflux is governed by mNCE, it is unknown whether elevated intracellular Na
+
([Na
+
]
i
) affects mitochondrial Ca
2+
uptake and bioenergetics. To monitor [Ca
2+
]
m
, mitochondria of guinea pig cardiac myocytes were loaded with rhod-2–acetoxymethyl ester (rhod-2 AM), and [Ca
2+
]
c
was monitored with indo-1 after dialyzing rhod-2 out of the cytoplasm. [Ca
2+
]
c
transients, elicited by voltage-clamp depolarizations, were accompanied by fast [Ca
2+
]
m
transients, whose amplitude (Δ) correlated linearly with Δ[Ca
2+
]
c
. Under β-adrenergic stimulation, [Ca
2+
]
m
decay was ≈2.5-fold slower than that of [Ca
2+
]
c
, leading to diastolic accumulation of [Ca
2+
]
m
when amplitude or frequency of Δ[Ca
2+
]
c
increased. The MCU blocker Ru360 reduced Δ[Ca
2+
]
m
and increased Δ[Ca
2+
]
c
, whereas the mNCE inhibitor CGP-37157 potentiated diastolic [Ca
2+
]
m
accumulation. Elevating [Na
+
]
i
from 5 to 15 mmol/L accelerated mitochondrial Ca
2+
decay, thus decreasing systolic and diastolic [Ca
2+
]
m
. In response to gradual or abrupt changes of workload, reduced nicotinamide-adenine dinucleotide (NADH) levels were maintained at 5 mmol/L [Na
+
]
i
, but at 15 mmol/L, the NADH pool was partially oxidized. The results indicate that (1) mitochondria take up Ca
2+
rapidly and contribute to fast buffering during a [Ca
2+
]
c
transient; and (2) elevated [Na
+
]
i
impairs mitochondrial Ca
2+
uptake, with consequent effects on energy supply and demand matching. The latter effect may have implications for cardiac diseases with elevated [Na
+
]
i
.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
322 articles.
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