Abstract
Mitochondria are critical for several cellular functions as they control metabolism, cell physiology, and cell death. The mitochondrial proteome consists of around 1500 proteins, the vast majority of which (about 99% of them) are encoded by nuclear genes, with only 13 polypeptides in human cells encoded by mitochondrial DNA. Therefore, it is critical for all the mitochondrial proteins that are nuclear-encoded to be targeted precisely and sorted specifically to their site of action inside mitochondria. These processes of targeting and sorting are catalysed by protein translocases that operate in each one of the mitochondrial sub-compartments. The main protein import pathway for the intermembrane space (IMS) recognises proteins that are cysteine-rich, and it is the only import pathway that chemically modifies the imported precursors by introducing disulphide bonds to them. In this manner, the precursors are trapped in the IMS in a folded state. The key component of this pathway is Mia40 (called CHCHD4 in human cells), which itself contains cysteine motifs and is subject to redox regulation. In this review, we detail the basic components of the MIA pathway and the disulphide relay mechanism that underpins the electron transfer reaction along the oxidative folding mechanism. Then, we discuss the key protein modulators of this pathway and how they are interlinked to the small redox-active molecules that critically affect the redox state in the IMS. We present also evidence that the mitochondrial redox processes that are linked to iron–sulfur clusters biogenesis and calcium homeostasis coalesce in the IMS at the MIA machinery. The fact that the MIA machinery and several of its interactors and substrates are linked to a variety of common human diseases connected to mitochondrial dysfunction highlight the potential of redox processes in the IMS as a promising new target for developing new treatments for some of the most complex and devastating human diseases.
Highlights
Mitochondria are essential organelles that participate in a diverse range of vital cellular functions ranging from energy production, to iron, macromolecule, and lipid biosynthesis.Mitochondria play a critical role in specific cell death modalities [1,2,3]
Calcium uptake into mitochondria of higher eukaryotes is mediated by the mitochondrial calcium uniporter (MCU), which is an inner mitochondrial membrane (IMM)-anchored calcium-conducting protein that functions in concert with regulatory proteins MICU1 (Mitochondrial calcium uptake 1)
We have highlighted some critical aspects of how redox regulation and signalling converge in the mitochondrial intermembrane space at the MIA pathway
Summary
Mitochondria are essential organelles that participate in a diverse range of vital cellular functions ranging from energy production, to iron, macromolecule, and lipid biosynthesis. Antioxidants 2021, 10, 592 which play a role in redox regulation [6] This “controlled exchange” of the IMS is due to the presence of porins in the OMM, which allow molecules of less than 5 kDa to freely diffuse, facilitating communication between mitochondria and other areas of the cell [7]. Alongside this “buffering” role between the cytosol and the matrix, IMS proteins are involved in the biogenesis, assembly, and stability of respiratory chain complexes, protein folding, lipid homeostasis, and the initiation of cell death through the release of proteins such as cytochrome c [3,8]. We will discuss the small redox molecules in the IMS and their interplay with proteins controlling the IMS-located import machinery
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