Calcium ions (Ca2+) are some of the most versatile signalling molecules, and they have many physiological functions, prominently including muscle contraction, neuronal excitability, cell migration and cell growth. By sequestering and releasing Ca2+, mitochondria serve as important regulators of cellular Ca2+. Mitochondrial Ca2+ also has other important functions, such as regulation of mitochondrial metabolism, ATP production and cell death. In recent years, identification of the molecular machinery regulating mitochondrial Ca2+ accumulation and efflux has expanded the number of (patho)physiological conditions that rely on mitochondrial Ca2+ homeostasis. Thus, expanding the understanding of the mechanisms of mitochondrial Ca2+ regulation and function in different cell types is an important task in biomedical research, which offers the possibility of targeting mitochondrial Ca2+ machinery for the treatment of several disorders.

The machineries, regulation and cellular functions of mitochondrial calcium.

Calcium at the Center of Cell Signaling: Interplay between Endoplasmic Reticulum, Mitochondria, and Lysosomes.

The phospholipid cardiolipin (CL) is an essential constituent of mitochondrial membranes and plays a role in many mitochondrial processes, including respiration and energy conversion Pathological changes in CL amount or species composition can have deleterious consequences for mitochondrial function and trigger the production of reactive oxygen species Signaling networks monitor mitochondrial function and trigger an adequate cellular response Here, we summarize the role of CL in cellular signaling pathways and focus on tissues with high-energy demand, like the heart CL itself was recently identified as a precursor for the formation of lipid mediators We highlight the concept of CL as a signaling platform CL is exposed to the outer mitochondrial membrane upon mitochondrial stress and CL domains serve as a binding site in many cellular signaling events During mitophagy, CL interacts with essential players of mitophagy like Beclin 1 and recruits the autophagic machinery by its interaction with LC3 Apoptotic signaling pathways require CL as a binding platform to recruit apoptotic factors such as tBid, Bax, caspase-8 CL required for the activation of the inflammasome and plays a role in inflammatory signaling As changes in CL species composition has been observed in many diseases, the signaling pathways described here may play a general role in pathology

/pdf/role-of-cardiolipin-in-mitochondrial-signaling-pathways-570ehoeutw.pdf

Role of Cardiolipin in Mitochondrial Signaling Pathways.

Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity

The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria

Mitochondrial Ca(2+) uptake, a process crucial for bioenergetics and Ca(2+) signaling, is catalyzed by the mitochondrial calcium uniporter. The uniporter is a multi-subunit Ca(2+)-activated Ca(2+) channel, with the Ca(2+) pore formed by the MCU protein and Ca(2+)-dependent activation mediated by MICU subunits. Recently, a mitochondrial inner membrane protein EMRE was identified as a uniporter subunit absolutely required for Ca(2+) permeation. However, the molecular mechanism and regulatory purpose of EMRE remain largely unexplored. Here, we determine the transmembrane orientation of EMRE, and show that its known MCU-activating function is mediated by the interaction of transmembrane helices from both proteins. We also reveal a second function of EMRE: to maintain tight MICU regulation of the MCU pore, a role that requires EMRE to bind MICU1 using its conserved C-terminal polyaspartate tail. This dual functionality of EMRE ensures that all transport-competent uniporters are tightly regulated, responding appropriately to a dynamic intracellular Ca(2+) landscape.

https://cdn.elifesciences.org/articles/15545/elife-15545-v5.pdf

Carole Willliams

Papers

Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex