Author response: MCU encodes the pore conducting mitochondrial calcium currents
Year: 2013
Type: peer-review
Abstract: Mitochondria are tiny organelles, less than a micrometre across, found inside almost all eukaryotic cells. Their main function is to act as the ‘power plant’ of the cell, generating adenosine triphosphate or ATP, which is the source of chemical energy for cellular processes. Beyond generating ATP, mitochondria perform many other functions: they contribute to various signalling pathways; they influence cellular differentiation; and they are involved in processes related to cell death. Mitochondria are quite distinctive in appearance—they are enclosed by two membranes, a porous outer one and a largely impermeable inner membrane. Most mitochondrial functions involve proteins that control the movement of various molecules and ions across the inner membrane. One particularly important ion that must pass through this membrane is calcium; once inside the mitochondria, these calcium ions regulate cell survival and the generation of ATP. Although several calcium import mechanisms exist, the best-studied pathway involves a pore-forming protein complex called the mitochondrial calcium uniporter. This ion channel has an exquisite selectivity, allowing only calcium into mitochondria even when other ions outnumber it a million-fold. Previously, researchers had identified several genes that are required for the formation of the uniporter, but it had not been established which of these encodes the central pore through which the calcium ions pass. Now, Chaudhuri et al. have shown that one of these—a gene called mitochondrial calcium uniporter (MCU)—codes for the protein subunit that creates the pore. Prior studies used optical methods or purified proteins to study genes encoding the uniporter complex, producing controversial results regarding pore identity. This study uses a much more direct assay, namely electrophysiology performed on mitochondrial inner membranes. To access the inner membrane, the authors stripped off the outer membrane from whole mitochondria, and made them expand. By using a technique called voltage-clamping, Chaudhuri et al. were able to precisely measure calcium ion movement through intact or mutated channels. This technique controls confounding factors and minimizes the effect of contaminants that can plague interpretation of data acquired by other methods. They showed that blocking the expression of the MCU gene reduced the flow of calcium ions through the uniporter, whereas increasing MCU expression increased calcium transport. One unique feature of the mitochondrial calcium uniporter is that it can be blocked by a dye called ruthenium red. Chaudhuri et al. used this property to confirm that the MCU gene encodes the pore-forming subunit of the channel complex—they identified a single point mutation in MCU that did not affect the channel’s ability to transport calcium ions, but did abolish its sensitivity to ruthenium red. Together, these results show that the MCU gene encodes the pore of the mitochondrial calcium uniporter, and should lead to further research into the physiology and structure of this channel.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W2986560034