MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism

Aras, Siddhesh; Bai, Minbo; Lee, Icksoo; Springett, Roger; Hüttemann, Maik; Grossman, Lawrence I.

doi:10.1016/j.mito.2014.10.003

Cited by 138 publications

(178 citation statements)

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“…We previously showed that MNRR1 is a component of a mitonuclear pathway whose signaling is altered under oxidative stress (5,6,24) and we now show that it functions in coordination with CHCHD10. CHCHD10 and MNRR1 belong to the twin CX 9 C family of proteins that primarily form scaffolds for the formation and the organization of the large macromolecular complexes found in mitochondria (32) such as cytochrome c oxidase, a complex composed of 14 subunits (33).…”

Section: Discussionmentioning

confidence: 53%

“…Mitochondrial MNRR1 interacts with cytochrome c oxidase (COX) and is required for optimal enzyme function. A stable knockdown of MNRR1 resembles a mitochondrial disease phenotype with decreased oxygen consumption, decreased cellular growth and mitochondrial membrane potential, and increased production of reactive oxygen species (ROS) (5). Nuclear MNRR1 regulates transcription of genes that harbor a conserved 13-bp sequence needed for the response to low oxygen levels that is termed the oxygen responsive element (ORE) (6).…”

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confidence: 99%

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The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

Purandare

Somayajulu

Hüttemann

et al. 2018

Journal of Biological Chemistry

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Coiled-coil-helix-coiled-coil-helix domaincontaining 10 (CHCHD10) and CHCHD2 (MNRR1) are homologous proteins with 58% sequence identity and belong to the twin CX 9 C family of proteins that mediate cellular stress responses. Despite the identification of several neurodegeneration-associated mutations in the CHCHD10 gene, few studies have assessed its physiological role. Here, we investigated CHCHD10's function as a regulator of oxidative phosphorylation in the mitochondria and the nucleus. We show that CHCHD10 co-purifies with cytochrome c oxidase (COX) and up-regulates COX activity by serving as a scaffolding protein required for MNRR1 phosphorylation, mediated by ARG (ABL proto-oncogene 2, non-receptor tyrosine kinase [ABL2]). The CHCHD10 gene was maximally transcribed in cultured cells at 8% oxygen, unlike MNRR1, which was maximally expressed at 4%, suggesting a fine-tuned oxygen-sensing system that adapts to the varying oxygen concentrations in the human body under physiological conditions. We show that nuclear CHCHD10 protein down-regulates the expression of genes harboring the oxygenresponsive element (ORE) in their promoters by interacting with and augmenting the activity of the largely uncharacterized transcriptional repressor CXXC finger protein 5 (CXXC5). We further show that two genetic CHCHD10 disease variants, G66V and P80L, in the mitochondria exhibit faulty interactions with MNRR1 and COX, reducing respiration and increasing reactive oxygen species (ROS), and in the nucleus abrogating transcriptional repression of ORE-containing genes. Our results reveal that CHCHD10 positively regulates mitochondrial respiration and contributes to transcriptional repression of ORE-containing genes in the nucleus, and that genetic CHCHD10 variants are impaired in these activities.CHCHD10 is a member of the twin CX 9 C family of proteins. This family, of which a number of members have displayed roles in disease (1), consists of proteins that contain two pairs of cysteine residues separated by 9 amino acids. These 4 cysteines form 2 disulfide bonds that stabilize the prototypical Coiled-coil Helix Coiled-coil Helix Domain (CHCHD) that traps CHCHD10 and other twin CX 9 C family members in the mitochondrial intermembrane space (IMS). Other members of this family include CHCHD4 (also called Mia40), necessary for import and proper folding of twin CX 9 C proteins in the IMS (2), and CHCHD3, which acts with CHCHD6 to stabilize mitochondrial cristae (3, 4). Another recently characterized member of this family is MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1; also called CHCHD2), a protein that is upregulated under hypoxic stress, and maximally so at 4% oxygen. 2Besides residing in the mitochondria, MNRR1 is also present in the nucleus. Mitochondrial MNRR1 interacts with cytochrome c oxidase (COX) and is required for optimal enzyme function. A stable knockdown of MNRR1 resembles a mitochondrial disease phenotype with decreased oxygen consumption, decreased cellular growth and mitochondrial membrane potential,...

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Section: Discussionmentioning

confidence: 53%

mentioning

confidence: 99%

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

Purandare

Somayajulu

Hüttemann

et al. 2018

Journal of Biological Chemistry

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“…B18 is the only subunit in complex I that is myristoylated (36) so it is interesting that for another CHCH domain protein (CHCHD3) myristoylation has been proposed to be important for transporting it across the outer membrane (37). Similarly, a CHCH domain protein (CHCHD2) required for the full activity of cytochrome c oxidase is translocated to the nucleus during hypoxia to regulate transcription of an isoform of cytochrome c oxidase subunit 4 (38) suggesting that the CHCH domain subunits of complex I may similarly have regulatory roles, perhaps acting through the redox status of their disulfide linkages.…”

Section: Discussionmentioning

confidence: 99%

Structure of subcomplex Iβ of mammalian respiratory complex I leads to new supernumerary subunit assignments

Zhu

King

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial complex I (proton-pumping NADH:ubiquinone oxidoreductase) is an essential respiratory enzyme. Mammalian complex I contains 45 subunits: 14 conserved "core" subunits and 31 "supernumerary" subunits. The structure of Bos taurus complex I, determined to 5-Å resolution by electron cryomicroscopy, described the structure of the mammalian core enzyme and allowed the assignment of 14 supernumerary subunits. Here, we describe the 6.8-Å resolution X-ray crystallography structure of subcomplex Iβ, a large portion of the membrane domain of B. taurus complex I that contains two core subunits and a cohort of supernumerary subunits. By comparing the structures and composition of subcomplex Iβ and complex I, supported by comparisons with Yarrowia lipolytica complex I, we propose assignments for eight further supernumerary subunits in the structure. Our new assignments include two CHCH-domain containing subunits that contain disulfide bridges between CX 9 C motifs; they are processed by the Mia40 oxidative-folding pathway in the intermembrane space and probably stabilize the membrane domain. We also assign subunit B22, an LYR protein, to the matrix face of the membrane domain. We reveal that subunit B22 anchors an acyl carrier protein (ACP) to the complex, replicating the LYR protein-ACP structural module that was identified previously in the hydrophilic domain. Thus, we significantly extend knowledge of how the mammalian supernumerary subunits are arranged around the core enzyme, and provide insights into their roles in biogenesis and regulation.CHCH domain | electron transport chain | LYR protein | mitochondria | NADH:ubiquinone oxidoreductase I n mammalian mitochondria, respiratory complex I (NADH: ubiquinone oxidoreductase) (1, 2) contains 45 subunits with a combined mass of 1 MDa (3-6). Fourteen core subunits, conserved from bacteria to humans, constitute the minimal complex I and catalyze the energy transducing reaction: NADH oxidation and ubiquinone reduction coupled to proton translocation across the inner membrane. Complex I is thus critical for mammalian metabolism: it oxidizes the NADH generated by the tricarboxylic acid cycle and β-oxidation, produces ubiquinol for the rest of the respiratory chain, and contributes to the proton-motive force that supports ATP synthesis and transport processes. Seven of the core subunits are hydrophilic proteins that are encoded in the nucleus and imported to mitochondria, and the other seven are hydrophobic, membrane-bound proteins (known as the ND subunits) that are encoded by the mitochondrial genome. These two sets of seven subunits form the two major domains of complex I, in the matrix and inner membrane, which confer its characteristic L shape.The protein composition of complex I from Bos taurus heart mitochondria has been characterized extensively, and is the blueprint for the human enzyme (3-6). In addition to the 14 core subunits it contains 31 supernumerary subunits (including two copies of the acyl-carrier protein, SDAP; ref. 2). Several supernumerary subunit...

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“…CHCHD10 and its 243 paralogue CHCHD2, which are encoded by genes localized on chromosomes 22q11.23 and 244 7p11.2, respectively, have emerged as a result of gene duplication during the evolution from 245 yeast to man [49]. Human CHCHD2 is essential for optimal respiratory activity [100][101][102], in 246 particular that of CIV [100,102]. CHCHD2 depletion reduces the expression of the mtDNA-247 encoded COX2 subunit of CIV [100].…”

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“…Moreover, the implication of CHCHD4 in the import of CHCHD2 and 266 CHCHD10, possibly through oxidation of the C-terminal (CX 9 C) 2 conserved motif (Figure 2), 267 remains to be formally demonstrated. However, the physical interaction between CHCHD4 268 and CHCHD2, as well as the inhibition of CHCHD2 expression by an ALR / ERV1 inhibitor 269 (MitoBloCK-6) [102,105], strongly suggest that the import of CHCHD2 depends on the 270 CHCHD4/ALR system. 271…”

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confidence: 99%

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

Modjtahedi

Tokatlidis

Dessen

et al. 2016

Trends in Biochemical Sciences

103

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Members of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family that carry (CX 9 C) type motifs are imported into the mitochondrion with the help of the disulfide relay-dependent MIA import pathway. These evolutionary-conserved proteins are emerging as new cellular factors that control mitochondrial respiration, redox regulation, lipid homeostasis or membrane ultrastructure and dynamics. Here, we discuss recent insights on the activity of known (CX 9 C) motif-carrying proteins in mammals and review current data implicating the MIA40/CHCHD4 import machinery in the regulation of their mitochondrial import. Recent findings and the identification of disease-associated mutations in specific (CX 9 C) motif-carrying proteins have highlighted members of this family of proteins as potential therapeutic targets in a variety of human disorders.

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MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism

Cited by 138 publications

References 30 publications

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

Structure of subcomplex Iβ of mammalian respiratory complex I leads to new supernumerary subunit assignments

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

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