The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space

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.

The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I

“…The CX 9 C motifs of these subunits form disulfide bonds that stabilize the helix-turn-helix structure of the subunits ( Figure 12B ) ( Ugalde et al, 2004 ; Longen et al, 2009 ; Szklarczyk et al, 2011 ). These subunits are imported into the IMS in an unfolded reduced form and subsequently folded and oxidized via the disulfide relay-dependent Mitochondrial Import and Assembly (MIA) pathway ( Figure 12C ) ( Mesecke et al, 2005 ; Fischer et al, 2013 ; Modjtahedi et al, 2016 ; Dickson-Murray et al, 2021 ). The electrons thus released during the oxidation are fed to CIV of the ETC via cytochrome c (cyt c ) or released as reactive oxygen species (ROS) ( Figure 12C ) ( Allen et al, 2005 ; Bihlmaier et al, 2007 ).…”

“…The electrons thus released during the oxidation are fed to CIV of the ETC via cytochrome c (cyt c ) or released as reactive oxygen species (ROS) ( Figure 12C ) ( Allen et al, 2005 ; Bihlmaier et al, 2007 ). The MIA pathway is regulated by the redox environment of the cell and interacts with several antioxidant systems ( Nakao et al, 2015 ; Kritsiligkou et al, 2017 ), as well as small molecule regulators ( Dickson-Murray et al, 2021 ).…”

Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells

“…Given the essentiality of the Cys-containing subunits and assembly factors of the ETC complexes, a correct redox homeostasis in the IMS is crucial for the biogenesis of the respiratory complexes. Thus, it is important to maintain the redox sensitive residues in the correct oxidation state for import and retention in the IMS, as well as for protein function ( Habich et al, 2019a ; Dickson-Murray et al, 2021 ). Considering the number of redox regulated IMS-located factors involved, this is particularly relevant for the assembly and metalation of CIV ( Khalimonchuk and Winge, 2008 ; Jett and Leary, 2018 ).…”

“…Considering the number of redox regulated IMS-located factors involved, this is particularly relevant for the assembly and metalation of CIV ( Khalimonchuk and Winge, 2008 ; Jett and Leary, 2018 ). Although there are still many open questions as to how the IMS maintains its redox homeostasis ( Dickson-Murray et al, 2021 ), it is clear that it contains several systems that ensure it, having glutathione as a central component ( Calabrese et al, 2017 ). One such mechanism for maintaining homeostasis in this compartment is the retro-translocation of reduced proteins back into the cytosol through the Tom40 import pore protein.…”

Mitochondrial Redox Regulations and Redox Biology of Mitochondria

“…Redox pathogenic aspects rather stem from the excessive superoxide/H 2 O 2 formation or from the insufficiency of the antioxidant mechanism (reviewed for a special case of pancreatic β-cells in [ 3 ]). The well-described intra-mitochondrial oxidative folding system is reported by Tokatlidis and colleagues [ 4 ], involving the Mia40 protein, which forms disulfide bridges on important proteins within the intermembrane space. The transcriptional regulation of mitochondrial redox equilibria is described by Scholtes and Giguère, presenting estrogen-related receptors as targetable redox sensors [ 5 ].…”