Mitochondrial COA7 is a heme-binding protein involved in the early stages of complex IV assembly

Formosa, Luke E.; Maghool, Shadi; Sharpe, Alice J.; Reljić, Boris; Muellner-Wong, Linden; Stroud, David A.; Ryan, Michael; Maher, M.J.

doi:10.1101/2021.06.10.447992

Cited by 2 publications

(2 citation statements)

References 80 publications

(134 reference statements)

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“…, 2019 ) ( Figure 5H ). The exact role of COA7 in the assembly of Complex IV was not known, but very recently, its heme-binding/chaperoning activity was proposed ( Formosa et al. , 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Discovery of bactericides as an acute mitochondrial membrane damage inducer

Houston

Sekine

Larsen

et al. 2021

MBoC

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Mitochondria evolved from endosymbiotic bacteria to become essential organelles of eukaryotic cells. The unique lipid composition and structure of mitochondrial membranes are critical for the proper functioning of mitochondria. However, stress responses that help maintain the mitochondrial membrane integrity are not well understood. One reason for this lack of insight is the absence of efficient tools to specifically damage mitochondrial membranes. Here, through a compound screen, we found that two bis-biguanide compounds, Chlorhexidine and Alexidine, modified the activity of the inner mitochondrial membrane (IMM)-resident protease OMA1 by altering the integrity of the IMM. These compounds are well-known bactericides whose mechanism of action has centered on their damage-inducing activity on bacterial membranes. We found Alexidine binds to the IMM likely through the electrostatic interaction driven by the membrane potential as well as an affinity for anionic phospholipids. Electron microscopic analysis revealed that Alexidine severely perturbated the cristae structure. Notably, Alexidine evoked a specific transcriptional/proteostasis signature that was not induced by other typical mitochondrial stressors, highlighting the unique property of Alexidine as a novel mitochondrial membrane stressor. Our findings provide a chemical-biological tool that should enable the delineation of mitochondrial stress-signaling pathways required to maintain the mitochondrial membrane homeostasis.

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Section: Discussionmentioning

confidence: 99%

Discovery of bactericides as an acute mitochondrial membrane damage inducer

Houston

Sekine

Larsen

et al. 2021

MBoC

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“…The first indication that COA7 is involved in COX biogenesis came from the fact that pathological variants in the COA7 gene are associated with mitochondrial CIV deficiency in humans (Lyons et al, 2016;Higuchi et al, 2018;Ban et al, 2021). Recent data suggest that it is a haem-binding protein involved in the early stages of COX assembly (Formosa et al, 2021). The right Cys composition in COA7 was shown to be crucial for IMS import efficiency and for its stability (Mohanraj et al, 2019).…”

Section: Role Of Ims Proteins In Complex IV Biogenesismentioning

confidence: 99%

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

Geldon

Fernández-Vizarra

Tokatlidis

2021

Front. Cell Dev. Biol.

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Mitochondria are double-membrane organelles that contain their own genome, the mitochondrial DNA (mtDNA), and reminiscent of its endosymbiotic origin. Mitochondria are responsible for cellular respiration via the function of the electron oxidative phosphorylation system (OXPHOS), located in the mitochondrial inner membrane and composed of the four electron transport chain (ETC) enzymes (complexes I-IV), and the ATP synthase (complex V). Even though the mtDNA encodes essential OXPHOS components, the large majority of the structural subunits and additional biogenetical factors (more than seventy proteins) are encoded in the nucleus and translated in the cytoplasm. To incorporate these proteins and the rest of the mitochondrial proteome, mitochondria have evolved varied, and sophisticated import machineries that specifically target proteins to the different compartments defined by the two membranes. The intermembrane space (IMS) contains a high number of cysteine-rich proteins, which are mostly imported via the MIA40 oxidative folding system, dependent on the reduction, and oxidation of key Cys residues. Several of these proteins are structural components or assembly factors necessary for the correct maturation and function of the ETC complexes. Interestingly, many of these proteins are involved in the metalation of the active redox centers of complex IV, the terminal oxidase of the mitochondrial ETC. Due to their function in oxygen reduction, mitochondria are the main generators of reactive oxygen species (ROS), on both sides of the inner membrane, i.e., in the matrix and the IMS. ROS generation is important due to their role as signaling molecules, but an excessive production is detrimental due to unwanted oxidation reactions that impact on the function of different types of biomolecules contained in mitochondria. Therefore, the maintenance of the redox balance in the IMS is essential for mitochondrial function. In this review, we will discuss the role that redox regulation plays in the maintenance of IMS homeostasis as well as how mitochondrial ROS generation may be a key regulatory factor for ETC biogenesis, especially for complex IV.

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Mitochondrial COA7 is a heme-binding protein involved in the early stages of complex IV assembly

Cited by 2 publications

References 80 publications

Discovery of bactericides as an acute mitochondrial membrane damage inducer

Discovery of bactericides as an acute mitochondrial membrane damage inducer

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

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