The mitochondrial Ca2+ uniporter: regulation by auxiliary subunits and signal transduction pathways.
Mitochondrial Ca(2+) homeostasis, the Ca(2+) influx-efflux balance, is responsible for the control of numerous cellular functions, including energy metabolism, generation of reactive oxygen species, spatiotemporal dynamics of Ca(2+) signaling, and cell growth and death. Recent discovery of the molecular identity of the mitochondrial Ca(2+) uniporter (MCU) provides new possibilities for application of genetic approaches to study the mitochondrial Ca(2+) influx mechanism in various cell types and tissues. In addition, the subsequent discovery of various auxiliary subunits associated with MCU suggests that mitochondrial Ca(2+) uptake is not solely regulated by a single protein (MCU), but likely by a macromolecular protein complex, referred to as the MCU-protein complex (mtCUC). Moreover, recent reports have shown the potential role of MCU posttranslational modifications in the regulation of mitochondrial Ca(2+) uptake through mtCUC. These observations indicate that mtCUCs form a local signaling complex at the inner mitochondrial membrane that could significantly regulate mitochondrial Ca(2+) handling, as well as numerous mitochondrial and cellular functions. In this review we discuss the current literature on mitochondrial Ca(2+) uptake mechanisms, with a particular focus on the structure and function of mtCUC, as well as its regulation by signal transduction pathways, highlighting current controversies and discrepancies.
Cardiovascular Research Center, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island; and.
Bong Sook
BS
Jhun
Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Jyotsna
J
Mishra
Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Sarah
S
Monaco
Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Deming
D
Fu
Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Wenmin
W
Jiang
Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Shey-Shing
SS
Sheu
Cardiovascular Research Center, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island; and jin.ouchi@lifespan.org jin_o-uchi@brown.edu.
Jin
J
O-Uchi
D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D015640:Ion Channel Gating; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D020836:Protein Structure, Quaternary; D021122:Protein Subunits; D012323:RNA Processing, Post-Transcriptional; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D015220:Calcium Channels; D021122:Protein Subunits; C034703:mitochondrial calcium uniporter; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
CCDC109A; Ca2+/calmodulin-dependent protein kinase II; MCUb; phosphorylation; proline-rich tyrosine kinase 2