Tim54p connects inner membrane assembly and proteolytic pathways in the mitochondrion

Hwang, David K.; Claypool, Steven M.; Leuenberger, D.; Tienson, Heather L.; Koehler, Carla M.

doi:10.1083/jcb.200706195

Cited by 45 publications

(40 citation statements)

References 57 publications

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“…Tomm22 is initially translated in the cytosol, then imported into the mitochondria, and integrated in the OMM . To investigate whether the phenotype observed in tomm22 s469 mutants was the result of inappropriate targeting of the Tomm22 s469 mutant protein, we used a yeast in vitro import system (Hwang et al, 2007). Radiolabeled WT or Tomm22 s469 mutant protein was imported into WT yeast mitochondria and the import reaction was split and carbonate-extracted at various pHs (supplementary material Fig.…”

Section: Tomm22mentioning

confidence: 99%

The mitochondrial import gene tomm22 is specifically required for hepatocyte survival and provides a liver regeneration model

Curado

Ober²,

Walsh

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARYUnderstanding liver development should lead to greater insights into liver diseases and improve therapeutic strategies. In a forward genetic screen for genes regulating liver development in zebrafish, we identified a mutant -oliver -that exhibits liver-specific defects. In oliver mutants, the liver is specified, bile ducts form and hepatocytes differentiate. However, the hepatocytes die shortly after their differentiation, and thus the resulting mutant liver consists mainly of biliary tissue. We identified a mutation in the gene encoding translocase of the outer mitochondrial membrane 22 (Tomm22) as responsible for this phenotype. Mutations in tomm genes have been associated with mitochondrial dysfunction, but most studies on the effect of defective mitochondrial protein translocation have been carried out in cultured cells or unicellular organisms. Therefore, the tomm22 mutant represents an important vertebrate genetic model to study mitochondrial biology and hepatic mitochondrial diseases. We further found that the temporary knockdown of Tomm22 levels by morpholino antisense oligonucleotides causes a specific hepatocyte degeneration phenotype that is reversible: new hepatocytes repopulate the liver as Tomm22 recovers to wild-type levels. The specificity and reversibility of hepatocyte ablation after temporary knockdown of Tomm22 provides an additional model to study liver regeneration, under conditions where most hepatocytes have died. We used this regeneration model to analyze the signaling commonalities between hepatocyte development and regeneration.

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Section: Tomm22mentioning

confidence: 99%

The mitochondrial import gene tomm22 is specifically required for hepatocyte survival and provides a liver regeneration model

Curado

Ober²,

Walsh

et al. 2010

Disease Models &Amp; Mechanisms

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“…Tim18 and Sdh3, which are homologous with each other, are involved in the assembly of the TIM22 complex on their own (19). Tim54 appears to be an adaptor protein that bridges the TIM22 core complex and small Tim proteins through direct interactions with Tim10 (22,23).…”

mentioning

confidence: 99%

Intramolecular Disulfide Bond of Tim22 Protein Maintains Integrity of the TIM22 Complex in the Mitochondrial Inner Membrane

Okamoto

Miyagawa

Shiota

et al. 2014

Journal of Biological Chemistry

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Background: Tim22 is a central component of the mitochondrial inner membrane protein insertion machinery TIM22 complex. Results: Lack of the disulfide bond of Tim22 destabilizes Tim22 and impairs substrate protein assembly. Conclusion:The disulfide bond of Tim22 has a role in stabilization of the TIM22 complex, which is important for the TIM22 protein assembly pathway. Significance: Tim40(Mia40)/Erv1-independent disulfide bond formation contributes to protein stability in mitochondria.

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“…Besides, mutants exhibit aberrant mitochondrial nucleoid structure and quantity, thus firmly establishing the role of Tim17 in the maintenance of mitochondrial genome and copy number. Earlier findings suggest that Tim54, a component of carrier translocase, plays an indirect role in maintaining the mtDNA stability by promoting the assembly of Yme1p (83). Similarly, we envision that the mtDNA instability in tim17 mutants could be a secondary effect due to the defective import of proteins required for stability and replication of mtDNA.…”

Section: Tim17 Maintains Mtdna and Tim23 Complex Integritymentioning

confidence: 79%

Role of Tim17 Transmembrane Regions in Regulating the Architecture of Presequence Translocase and Mitochondrial DNA Stability

Matta

Pareek

Bankapalli

et al. 2017

Molecular and Cellular Biology

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Mitochondrial life cycle and protein import are intricate cellular processes, which require precise coordination between the transport machineries of outer and inner mitochondrial membranes. Presequence translocase performs the indispensable function of translocating preproteins having N-terminal targeting sequences across the inner membrane. Tim23 forms the core of the voltage-gated import channel, while Tim17 is presumed to maintain the stoichiometry of the translocase. However, mechanistic insights into how Tim17 coordinates these regulatory events within the complex remained elusive. We demonstrate that Tim17 harbors conserved G/AXXXG/A motifs within its transmembrane regions and plays an imperative role in the translocase assembly through interaction with Tim23. Tandem motifs are highly essential, as most of the amino acid substitutions lead to nonviability due to the complete destabilization of the TIM23 channel. Importantly, Tim17 transmembrane regions regulate the dynamic assembly of translocase to form either the TIM23 (PAM)-complex or TIM23 (SORT)-complex by recruiting the presequence translocase-associated motor (PAM) machinery or Tim21, respectively. To a greater significance, tim17 mutants displayed mitochondrial DNA (mtDNA) instability, membrane potential loss, and defective import, resulting in organellar dysfunction. We conclude that the integrity of Tim17 transmembrane regions is critical for mitochondrial function and protein turnover.KEYWORDS mitochondria, presequence translocase, mtDNA stability, preprotein import, membrane potential T he vast majority of mitochondrial proteins are encoded by nuclear genes and synthesized on cytosolic ribosomes with an amino-terminal positively charged cleavable signal sequence. The efficient import of mitochondrial proteins requires precise coordination between the translocases of the outer membrane (TOM complex) and the inner membrane (TIM23 complex) (1-9). After initial recognition and transport through TOM complex, these preproteins are actively sorted based on their destination. The preproteins directed toward the matrix compartment possess an N-terminal positively charged presequence and are imported into the matrix compartment with the aid of presequence translocase (TIM23 complex) (1-10). The core of presequence translocase consists of a membrane-bound channel component formed by . Tim23 and Tim17 are phylogenetically related integral membrane proteins and have similar transmembrane topology. Tim23 contributes to the formation of voltage-gated protein-conducting pores, while the evidence suggests that Tim17 is majorly involved in regulating the channel activity (16)(17)(18)(19)(20)(21)(22)(23). Other components such as Tim50 and Tim21 act as receptors and coordinate with the intermembrane space (IMS) domain of Tim23 to facilitate preprotein recognition and transfer from the TOM complex to presequence translocase (16, 17, 22, 24-32). Mgr2 has been recently

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Tim54p connects inner membrane assembly and proteolytic pathways in the mitochondrion

Cited by 45 publications

References 57 publications

The mitochondrial import gene tomm22 is specifically required for hepatocyte survival and provides a liver regeneration model

The mitochondrial import gene tomm22 is specifically required for hepatocyte survival and provides a liver regeneration model

Intramolecular Disulfide Bond of Tim22 Protein Maintains Integrity of the TIM22 Complex in the Mitochondrial Inner Membrane

Role of Tim17 Transmembrane Regions in Regulating the Architecture of Presequence Translocase and Mitochondrial DNA Stability

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