Cardiolipin-dependent Reconstitution of Respiratory Supercomplexes from Purified Saccharomyces cerevisiae Complexes III and IV

Bazán, Soledad; Mileykovskaya, Eugenia; Mallampalli, Venkata; Heacock, Philip; Sparagna, Genevieve C.; Dowhan, William

doi:10.1074/jbc.m112.425876

Cited by 127 publications

(114 citation statements)

References 54 publications

(51 reference statements)

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…Many IMM proteins have CL-binding domains, thus limiting free exchange and redistribution of the phospholipid to the OMM. [28][29][30][31][32][33][34][35][36] In some of these proteins, CL molecules are buried 'deeply' within multimeric protein complexes (like in electron-transporting respirasomes 35,36 ), whereas in the others the affinity and accessibility of CL for translocations seem to be less restricted (e.g., TIM40 37 ). Although the exact amounts of CL in the two pools -free versus bound -have not been established, it is likely that in normally functioning mitochondria, the majority of the IMM CLs is not readily mobilized.…”

Section: Discussionmentioning

confidence: 99%

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

Kagan¹,

Jiang²,

Huang³

et al. 2016

Cell Death Differ

164

133

View full text Add to dashboard Cite

Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified as a mitophageal signal recognized by the microtubuleassociated protein 1 light chain 3. However, the CL-translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH-SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, implicating fission-fusion dynamics in mitophagy regulation.

show abstract

Section: Discussionmentioning

confidence: 99%

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

Kagan¹,

Jiang²,

Huang³

et al. 2016

Cell Death Differ

164

133

View full text Add to dashboard Cite

show abstract

“…Phospholipids, in particular CL, the mitochondrion-specific phospholipid, are essential for the stabilization and function of the bc 1 complex (49) as well as for the stabilization of the III 2 / IV 2 SC in yeast (50) and the III 2 /IV and I/III 2 /IV SC in mammalian cells (51,52). As we have observed a bc 1 complex deficiency with an impaired formation of the III 2 /IV SC in C11orf83-deficient cells, we hypothesized that C11orf83 could either be involved in phospholipid metabolism or interact with mitochondrial phospholipids.…”

Section: C11orf83 Is An Integral Mitochondrial Inner Membrane Proteinmentioning

confidence: 99%

C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved in bc₁ Complex Assembly and Supercomplex Stabilization

Desmurs

Foti

Raemy

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

e Mammalian mitochondria may contain up to 1,500 different proteins, and many of them have neither been confidently identified nor characterized. In this study, we demonstrated that C11orf83, which was lacking experimental characterization, is a mitochondrial inner membrane protein facing the intermembrane space. This protein is specifically associated with the bc 1 complex of the electron transport chain and involved in the early stages of its assembly by stabilizing the bc 1 core complex. C11orf83 displays some overlapping functions with Cbp4p, a yeast bc 1 complex assembly factor. Therefore, we suggest that C11orf83, now called UQCC3, is the functional human equivalent of Cbp4p. In addition, C11orf83 depletion in HeLa cells caused abnormal crista morphology, higher sensitivity to apoptosis, a decreased ATP level due to impaired respiration and subtle, but significant, changes in cardiolipin composition. We showed that C11orf83 binds to cardiolipin by its ␣-helices 2 and 3 and is involved in the stabilization of bc 1 complex-containing supercomplexes, especially the III 2 /IV supercomplex. We also demonstrated that the OMA1 metalloprotease cleaves C11orf83 in response to mitochondrial depolarization, suggesting a role in the selection of cells with damaged mitochondria for their subsequent elimination by apoptosis, as previously described for OPA1. Mitochondria are membrane-enclosed organelles composed of several compartments which perform specialized and interconnected functions such as oxidative phosphorylation (OXPHOS), cell death, or carbohydrate and fatty acid metabolisms. OXPHOS, which provides most of the ATP used by the cell, takes place in the inner membrane (IM) and involves five complexes. Redox reactions are carried out by complex I (NADH: ubiquinone oxidoreductase; EC 1.6.5.3), complex II (succinate: ubiquinone oxidoreductase; EC 1.3.5.1), complex III (ubiquinol: ferricytochrome c oxidoreductase; EC 1.10.2.2), and complex IV (cytochrome c oxidoreductase; EC 1.9.3.1). Then, the ATP synthase, complex V (F 1 F 0 ATPase; EC 3.6.3.14), uses the energy released by respiration for ATP generation. The assembly of the OXPHOS complexes requires additional nuclear proteins called assembly factors (1). The physiological importance of these assembly factors is proven by the number of human diseases associated with mutations in genes encoding them (1).Complex III, also called cytochrome bc 1 complex, is a central component of the electron transport chain (ETC). It transfers electrons from coenzyme Q reduced either by complex I through NADH-linked substrates or by complex II through reduced flavin adenine dinucleotide (FADH 2 )-linked substrates to cytochrome c. The mammalian bc 1 complex, which forms as a stable dimer (2), is composed of 11 subunits, among which only MT-CYB is encoded by the mitochondrial genome (3, 4). Most of the work on the bc 1 complex assembly has been performed with Saccharomyces cerevisiae and has shown this to be a multistep process involving several subcomplexes and assembly factors (5...

show abstract

“…CL is essential for the function of many proteins residing in mitochondrial membranes. It interacts with proteins in the mitochondrial inner membrane such as the ADP/ATP carrier and respiratory chain complexes facilitating formation of respiratory supercomplexes that are essential for energy production by respiration (13)(14)(15)(16). However, the importance of CL extends beyond respiration, as it also modulates the function of the general translocase of the MOM, the TOM complex (12).…”

mentioning

confidence: 99%

Genome-Wide Screens in Saccharomyces cerevisiae Highlight a Role for Cardiolipin in Biogenesis of Mitochondrial Outer Membrane Multispan Proteins

Sauerwald

Jores

Eisenberg-Bord

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

A special group of mitochondrial outer membrane (MOM) proteins spans the membrane several times via multiple helical segments. Such multispan proteins are synthesized on cytosolic ribosomes before their targeting to mitochondria and insertion into the MOM. Previous work recognized the import receptor Tom70 and the mitochondrial import (MIM) complex, both residents of the MOM, as required for optimal biogenesis of these proteins. However, their involvement is not sufficient to explain either the entire import pathway or its regulation. To identify additional factors that are involved in the biogenesis of MOM multispan proteins, we performed complementary high-throughput visual and growth screens in Saccharomyces cerevisiae. Cardiolipin (CL) synthase (Crd1) appeared as a candidate in both screens. Our results indeed demonstrate lower steady-state levels of the multispan proteins Ugo1, Scm4, and Om14 in mitochondria from crd1⌬ cells. Importantly, MOM single-span proteins were not affected by this mutation. Furthermore, organelles lacking Crd1 had a lower in vitro capacity to import newly synthesized Ugo1 and Scm4 molecules. Crd1, which is located in the mitochondrial inner membrane, condenses phosphatidylglycerol together with CDP-diacylglycerol to obtain de novo synthesized CL molecules. Hence, our findings suggest that CL is an important component in the biogenesis of MOM multispan proteins.

show abstract

Cardiolipin-dependent Reconstitution of Respiratory Supercomplexes from Purified Saccharomyces cerevisiae Complexes III and IV

Cited by 127 publications

References 54 publications

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved in bc₁ Complex Assembly and Supercomplex Stabilization

Genome-Wide Screens in Saccharomyces cerevisiae Highlight a Role for Cardiolipin in Biogenesis of Mitochondrial Outer Membrane Multispan Proteins

Contact Info

Product

Resources

About

Cardiolipin-dependent Reconstitution of Respiratory Supercomplexes from Purified Saccharomyces cerevisiae Complexes III and IV

Cited by 127 publications

References 54 publications

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved in bc1 Complex Assembly and Supercomplex Stabilization

Genome-Wide Screens in Saccharomyces cerevisiae Highlight a Role for Cardiolipin in Biogenesis of Mitochondrial Outer Membrane Multispan Proteins

Contact Info

Product

Resources

About

C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved in bc₁ Complex Assembly and Supercomplex Stabilization