Tam41 Is a CDP-Diacylglycerol Synthase Required for Cardiolipin Biosynthesis in Mitochondria

Tamura, Yasushi; Harada, Yoshihiro; Nishikawa, Shuh-ichi; Yamano, Koji; Kamiya, Megumi; Shiota, Takuya; Kuroda, Takuya; Kuge, Osamu; Sesaki, Hiromi; Imai, Keisuke; Tomii, Kentaro; Endo, Toshiya

doi:10.1016/j.cmet.2013.03.018

Cited by 145 publications

(143 citation statements)

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“…7C) (albeit with reduced levels of AAC). Tam41 is a CDP-diacylglycerol synthase required for CL biosynthesis in mitochondria, and thus, like the ⌬crd1, ⌬tam41 mitochondria are deficient in CL (31). Interestingly, despite being reduced in levels, a population of Taz1, an enzyme involved in remodeling of CL, was recovered in association with the affinity-purified rcf1 His R67A protein (Fig.…”

Section: R67amentioning

confidence: 99%

Mutational Analysis of the QRRQ Motif in the Yeast Hig1 Type 2 Protein Rcf1 Reveals a Regulatory Role for the Cytochrome c Oxidase Complex

Garlich

Strecker

Wittig

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerThe yeast Rcf1 protein is a member of the conserved family of proteins termed the hypoxia-induced gene (domain) 1 (Hig1 or HIGD1) family. Rcf1 interacts with components of the mitochondrial oxidative phosphorylation system, in particular the cytochrome bc 1 (complex III)-cytochrome c oxidase (complex IV) supercomplex (termed III-IV) and the ADP/ATP carrier proteins. Rcf1 plays a role in the assembly and modulation of the activity of complex IV; however, the molecular basis for how Rcf1 influences the activity of complex IV is currently unknown. Hig1 type 2 isoforms, which include the Rcf1 protein, are characterized in part by the presence of a conserved motif, (Q/I)X 3 (R/H)XRX 3 Q, termed here the QRRQ motif. We show that mutation of conserved residues within the Rcf1 QRRQ motif alters the interactions between Rcf1 and partner proteins and results in the destabilization of complex IV and alteration of its enzymatic properties. Our findings indicate that Rcf1 does not serve as a stoichiometric component, i.e. as a subunit of complex IV, to support its activity. Rather, we propose that Rcf1 serves to dynamically interact with complex IV during its assembly process and, in doing so, regulates a late maturation step of complex IV. We speculate that the Rcf1/Hig1 proteins play a role in the incorporation and/or remodeling of lipids, in particular cardiolipin, into complex IV and. possibly, other mitochondrial proteins such as ADP/ATP carrier proteins.Mitochondria are specialized organelles that are a nexus for several critical cellular pathways, including the aerobic production of energy through oxidative phosphorylation (OXPHOS) 2

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Section: R67amentioning

confidence: 99%

Mutational Analysis of the QRRQ Motif in the Yeast Hig1 Type 2 Protein Rcf1 Reveals a Regulatory Role for the Cytochrome c Oxidase Complex

Garlich

Strecker

Wittig

et al. 2017

Journal of Biological Chemistry

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“…Mitochondria are also equipped with a family of carriers that facilitate the transport of small soluble molecules like amino acids, nucleotides, and vitamins across the mitochondrial inner membrane, necessary for the interdependent metabolism at both sides of the mitochondrial double membrane (76,77). Mitochondria also play an important role in lipid metabolism (28,29,31,78): it is the site of synthesis of the mitochondrial-specific PLs, CL, and PG, generated from PA, which is imported from the ER (Fig. 1).…”

Section: Making Mitochondrial Membranes: the Contribution Of Er-mitocmentioning

confidence: 99%

“…The first methylation is carried out by Cho2 and the second and third by Opi3. PA is also transported to the mitochondria where it is converted to CDP-DAG by the activity of the mitochondrial CDP-DAG synthase, Tam41 (28), for subsequent synthesis of the mitochondrial-specific lipids, phosphatidylglycerol (PG) by Pgs1/Gep4 and cardiolipin (CL) by Crd1 ( Fig. 1) (29)(30)(31).…”

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confidence: 99%

Lipid synthesis and membrane contact sites: a crossroads for cellular physiology

Fernández-Murray

McMaster

2016

Journal of Lipid Research

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high throughput analyses, makes this yeast a powerful organism to unveil the intricacies of this field. The yeast S. cerevisiae has played a foundational role in the field of molecular and cellular biology of lipids, including the identification of membrane contact sites (MCSs) and how they link lipid metabolism with organelle dynamics. We present advances in two topics where extensive and outstanding contributions have recently been made where their relevance transcends the yeast lipid field. We first review new information about the phosphatidic acid (PA) phosphatase, Pah1, the yeast homolog of human lipin, and its role in directing lipid flux into membrane synthesis or storage. We review the contribution of Pah1 to lipid droplet (LD) formation and its interaction with the seipin complex, Fld1/Ldb16, to regulate endoplasmic reticulum (ER)-LD contact site dynamics. Second, we recapitulate recent developments revealing MCS connections between the ER and mitochondria with other cellular compartments, and how these intersect with the maintenance of lipid homeostasis. Furthermore, we explore MCS redundancies that allow cells to cope with changing metabolic demand. PA METABOLISM CO-COORDINATES MEMBRANE AND LD SYNTHESISPA is the common precursor for the synthesis of membrane phospholipids (PLs) and the major component of The pervasive importance of lipids in cell biology has become evident. From structural roles defining cellular compartments and surfaces with specific biological properties to functional roles in signal transduction processes and modulation of regulatory networks, the involvement of lipids in varied cellular functions is well-established. Concurrently, we have gained a broad understanding about the repertoire of proteins involved in synthesis, degradation, transport, and sensing of lipids, as well as the regulatory mechanisms that interconnect lipid metabolism with other cellular processes. The amenability of Saccharomyces cerevisiae to classical approaches of molecular genetics, and toThe work on the science described in this review was supported by a Discovery Grant from the Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada to C.R.M. Manuscript received 19 July 2016 and in revised form 6 August 2016. Published, JLR Papers in Press, August 12, 2016 DOI 10.1194 Lipid synthesis and membrane contact sites: a crossroads for cellular physiology Abbreviations: cER, cortical endoplasmic reticulum; ChiMERA, construct helping in mitochondria-endoplasmic reticulum association; CL, cardiolipin; DAG, diacylglycerol; EMC, endoplasmic reticulum membrane protein complex; ER, endoplasmic reticulum; ERMES, endoplasmic reticulum-mitochondria encounter structure; HOPS, homotypic fusion and vacuole protein sorting; Lam, lipid transfer protein anchored at a membrane contact site; LD, lipid droplet; Ltc, lipid transfer at contact site; LTP, lipid transfer protein; Mcp, maintenance of mitochondrial morphology 10 complementing protein; M...

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“…Liposomes based reconstitution of the purified translocase revealed that the minimal unit for preprotein integration into the inner membrane is the four-subunit TIM23 complex, a cardiolipin-rich membrane, and a membrane potential. Cardiolipin is the characteristic dimeric phospholipid of mitochondrial inner membrane (Acehan et al, 2011; Bihlmaier et al., 2008; Corcelli et al, 2010;Tamura et al, 2013). Preproteins following this insertion pathway into the inner membrane contain a hydrophobic sorting signal behind the matrix-targeting signal.…”

Section: Devanjan Sinhamentioning

confidence: 99%

Post Genomics Identification of Blood Stage Invasins of Plasmodium Falciparum

Chauhan¹

2017

Proceedings of the Indian National Science Academy

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Human mitochondria require ~1500 proteins for its constitutive functions. However, the mitochondrial genome is gene deficient and most of the mitochondrial proteome is nuclear encoded and transported into the organelle. Import of majority of mitochondrial proteome is mediated by presequence pathway and requires functional interplay between a subset of molecular chaperones, along with accessory factors. Although detailed analysis has been carried out in yeast system, our understanding of human mitochondrial proteome maintenance has been severely limited by the absence of significant structural and functional information on the organization TIM23 complex in humans. Recent studies have revealed the presence of multiple presequence translocases in human mitochondria that show considerable diversity in their substrate and physiological specificity. The core organization and inter-molecular interactions between these machineries seems to be evolutionary conserved. These translocases have principally diversified due to divergence of Hsp70 co-chaperones and channel component Tim17. Another important feature associated with human mitochondrial translocases, which in most cases are absent in lower eukaryotes, is its multifunctionality. Other than housekeeping protein import, human mitochondrial translocases have gained secondary functions such asinvolvment in ROS sensing and regulation of redox balance, modulation of cellular sensitivity to xenobiotic drugs, maintenance of mitochondrial DNA, assembly of respiratory complexes' and import of non-canonical mitochondrial substrates. The origin of multifunctionality is indicative towards the possibility of functional connections between mitochondrial protein import and regulation of cellular pathways; hence, opening up new avenues of future research. Keywords IntroductionMitochondria are endosymbiotic cellular organelle enclosed in double membrane and form an integral part of eukaryotic cells. The word mitochondrion comes from the Greek ìßôïò, mitos, i.e. "thread", and ÷ïíäñßïí, chondrion, i.e. "granule". The term "mitochondria" was coined by Carl Benda in 1898 (cited in Margulis, 1970). Benjamin F. Kingsbury (1912) first related these organelles with cell respiration (cited in Sagan, 1967), followed by Otto Heinrich Warburg (Ernster and Schatz, 1981; Gray et al., 1999). In addition to supplying cellular energy, mitochondria are involved in other tasks such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth (Gray et al., 1999). Mitochondria have been implicated in several human diseases, including mitochondrial disorders and cardiac dysfunction, and may play a role in the aging process (Fulda et al., 2010; Gulbins et al., 2003; Hayashi et al., 2009; Kroemer, 2006; Lesnefsky et al., 2001; McBride et al., 2006).Mitochondrial genomes are very small and show a great deal of variation as a result of divergent evolution (Ernster and Schatz, 1981; Henze and Martin, 2003; Peng et al., 2005). The human mitochondrial geno...

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Tam41 Is a CDP-Diacylglycerol Synthase Required for Cardiolipin Biosynthesis in Mitochondria

Cited by 145 publications

References 51 publications

Mutational Analysis of the QRRQ Motif in the Yeast Hig1 Type 2 Protein Rcf1 Reveals a Regulatory Role for the Cytochrome c Oxidase Complex

Mutational Analysis of the QRRQ Motif in the Yeast Hig1 Type 2 Protein Rcf1 Reveals a Regulatory Role for the Cytochrome c Oxidase Complex

Lipid synthesis and membrane contact sites: a crossroads for cellular physiology

Post Genomics Identification of Blood Stage Invasins of Plasmodium Falciparum

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