Glutathionylated and Fe–S cluster containing hMIA40 (CHCHD4) regulates ROS and mitochondrial complex III and IV activities of the electron transport chain

Thiriveedi, Venkata Ramana; Mattam, Ushodaya; Pattabhi, Prasad; Bisoyi, Vandana; Talari, Noble Kumar; Krishnamoorthy, T.M.; Sepuri, Naresh Babu V.

doi:10.1016/j.redox.2020.101725

Cited by 16 publications

(8 citation statements)

References 47 publications

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“…Studies have shown that Complex I and Complex III containing super-complex hastens the delivery of electrons via CoQ and thereby increases electron transfer efficiency 26 . To further understand the lowered state III respiration displayed by LDM, we measured super complex I + III and II + III coupled activities described previously [27][28][29] . Super complex I + III and II + III activities were carried out using equal concentrations of LDM and CM as described in the methods section.…”

Section: Ldm Is Bioenergetically Differentiatedmentioning

confidence: 99%

Lipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats

et al. 2023

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Mitochondria empower the liver to regulate lipid homeostasis by enabling fatty acid oxidation during starvation and lipogenesis during nutrient-rich conditions. It is unknown if mitochondria can seamlessly regulate these two distinct processes or if two discrete populations of mitochondria achieve these two functions in the liver. For the first time in the liver, we report the isolation of two distinct populations of mitochondria from male Wistar rats on an ad-libitum diet: cytoplasmic mitochondria and lipid droplet-associated mitochondria. Our studies show that while lipid droplet mitochondria exhibit higher fatty acid oxidation and are marked by enhanced levels of pACC2, MFN2, and CPT1 activity, cytoplasmic mitochondria are associated with higher respiration capacity. Notably, lipid droplet-associated mitochondria isolated from a non-alcoholic fatty liver disease (NAFLD) rat model are compromised for fatty acid oxidation. We demonstrate the importance of functional segregation of mitochondria as any aberration in lipid droplet-associated mitochondria may lead to NAFLD.

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Section: Ldm Is Bioenergetically Differentiatedmentioning

confidence: 99%

Lipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats

et al. 2023

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“…On the one hand, the import of proteins to the mitochondrial matrix relies on a disulfide-exchange relay system; on the other hand, GRX1 has been identified to reside in IMS, pinpointing the observation that S-glutathionylation may play a crucial role in IMS [ 70 ]. However, a recent study showed that the human S-glutathionylation of MIA40, an IMS import receptor, facilitates the maintenance of ROS levels and the optimal function of CIII and CIV [ 71 ]. This mechanism highlights the interconnection between ROS levels, protein S-glutathionylation and mitochondrial respiration ( Figure 3 ).…”

Section: Protein S-glutathionylationmentioning

confidence: 99%

S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases

Vrettou

Wirth

2022

IJMS

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Redox post-translational modifications are derived from fluctuations in the redox potential and modulate protein function, localization, activity and structure. Amongst the oxidative reversible modifications, the S-glutathionylation of proteins was the first to be characterized as a post-translational modification, which primarily protects proteins from irreversible oxidation. However, a growing body of evidence suggests that S-glutathionylation plays a key role in core cell processes, particularly in mitochondria, which are the main source of reactive oxygen species. S-nitrosylation, another post-translational modification, was identified >150 years ago, but it was re-introduced as a prototype cell-signaling mechanism only recently, one that tightly regulates core processes within the cell’s sub-compartments, especially in mitochondria. S-glutathionylation and S-nitrosylation are modulated by fluctuations in reactive oxygen and nitrogen species and, in turn, orchestrate mitochondrial bioenergetics machinery, morphology, nutrients metabolism and apoptosis. In many neurodegenerative disorders, mitochondria dysfunction and oxidative/nitrosative stresses trigger or exacerbate their pathologies. Despite the substantial amount of research for most of these disorders, there are no successful treatments, while antioxidant supplementation failed in the majority of clinical trials. Herein, we discuss how S-glutathionylation and S-nitrosylation interfere in mitochondrial homeostasis and how the deregulation of these modifications is associated with Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and Friedreich’s ataxia.

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“…Through this post-translational modification, cysteine residues in IMS proteins could be modified by ROS and RNS, with implications for redox signalling. Recently, it has been proposed that human Mia40 (CHCHD4) undergoes glutathionylation, which is then capable of transferring electrons directly to cytochrome c [ 74 ]. These authors suggest that glutathionylation of human Mia40 occurs to control the levels of ROS levels normally produced by electron transfer complexes III and IV.…”

Section: Small Redox Molecules and Redox Homeostasis In The Imsmentioning

confidence: 99%

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

et al. 2021

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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.

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Glutathionylated and Fe–S cluster containing hMIA40 (CHCHD4) regulates ROS and mitochondrial complex III and IV activities of the electron transport chain

Cited by 16 publications

References 47 publications

Lipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats

Lipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats

S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases

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

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