MICU2, a Paralog of MICU1, Resides within the Mitochondrial Uniporter Complex to Regulate Calcium Handling

Mitochondrial calcium uptake is present in nearly all vertebrate tissues and is believed to be critical in shaping calcium signaling, regulating ATP synthesis and controlling cell death. Calcium uptake occurs through a channel called the uniporter that resides in the inner mitochondrial membrane. Recently, we used comparative genomics to identify MICU1 and MCU as the key regulatory and putative pore-forming subunits of this channel, respectively. Using bioinformatics, we now report that the human genome encodes two additional paralogs of MICU1, which we call MICU2 and MICU3, each of which likely arose by gene duplication and exhibits distinct patterns of organ expression. We demonstrate that MICU1 and MICU2 are expressed in HeLa and HEK293T cells, and provide multiple lines of biochemical evidence that MCU, MICU1 and MICU2 reside within a complex and cross-stabilize each other's protein expression in a cell-type dependent manner. Using in vivo RNAi technology to silence MICU1, MICU2 or both proteins in mouse liver, we observe an additive impairment in calcium handling without adversely impacting mitochondrial respiration or membrane potential. The results identify MICU2 as a new component of the uniporter complex that may contribute to the tissue-specific regulation of this channel.National Institutes of Health (U.S.) (GM0077465)National Institutes of Health (U.S.) (DK080261

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Accumulation of calcium and phosphate stimulated by carboxylic antibiotics into mitochondria

Carboxylic ionophores such as nigericin, dianemycin, the monensins and compounds Lilly A 217 or X-537 A, stimulate an electron-transport dependent accumulation of Ca 2+ and phosphate into mitochondria. Ion accumulation is stimulated under conditions of limited Ca 2+ loading imposed by phosphate in the presence of β-hydroxybutyrate. Carboxylic ionophores do not affect divalent ion uptake when β-hydroxybutyrate is replaced for by succinate. They block Ca 2+ and phosphate accumulation when energy is provided from the hydrolysis of ATP, or from the oxidation of glutamate, α-ketoglutarate, pyruvate or glutamate+malate. Nigericin-like antibiotics also transform the indefinite prolongation of state 3 respiration induced by Ca 2+ and phosphate on β-hydroxybutyrate oxidation, into tightly coupled state 3 to 4 transitions. Evidence suggests that electrophoretic Ca 2+ transport occurs in parallel with proton or K + carriers. The anion movements associated to Ca 2+ uptake are most probably driven by the existent ΔpH across the mitochondrial membrane.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44799/1/10863_2005_Article_BF01516075.pd