Directed import of macromolecules into mitochondria

Kamenski, Piotr; Vinogradova, Elizaveta; Krasheninnikov, Igor A.; Tarasov, Iu A

doi:10.1134/s0026893307020021

Cited by 4 publications

(4 citation statements)

References 99 publications

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“…More than 98% of the human mitochondrial protein pool is nuclear-encoded and transported into the mitochondria through highly complex import machinery spanning the outer membrane, inner membrane, and the intermembrane space (2,3). At the inner membrane, TIM23 complex forms the sole gateway for translocation of precursor proteins into the matrix, which accounts for ϳ60% of the total imported proteins (4,5). The TIM23 complex comprises of two components: membrane-embedded Tim23 core channel and the motor component.…”

Section: From the Department Of Biochemistry Indian Institute Of Scimentioning

confidence: 99%

Functional Diversity of Human Mitochondrial J-proteins Is Independent of Their Association with the Inner Membrane Presequence Translocase

Sinha

Srivastava

D’Silva

2016

Journal of Biological Chemistry

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Mitochondrial J-proteins play a critical role in governing Hsp70 activity and, hence, are essential for organellar protein translocation and folding. In contrast to yeast, which has a single J-protein Pam18, humans involve two J-proteins, DnaJC15 and DnaJC19, associated with contrasting cellular phenotype, to transport proteins into the mitochondria. Mutation in DnaJC19 results in dilated cardiomyopathy and ataxia syndrome, whereas expression of DnaJC15 regulates the response of cancer cells to chemotherapy. In the present study we have comparatively assessed the biochemical properties of the J-protein paralogs in relation to their association with the import channel. Both DnaJC15 and DnaJC19 formed two distinct subcomplexes with Magmas at the import channel. Knockdown analysis suggested an essential role for Magmas and DnaJC19 in organellar protein translocation and mitochondria biogenesis, whereas DnaJC15 had dispensable supportive function. The J-proteins were found to have equal affinity for Magmas and could stimulate mitochondrial Hsp70 ATPase activity by equivalent levels. Interestingly, we observed that DnaJC15 exhibits bifunctional properties. At the translocation channel, it involves conserved interactions and mechanism to translocate the precursors into mitochondria. In addition to protein transport, DnaJC15 also showed a dual role in yeast where its expression elicited enhanced sensitivity of cells to cisplatin that required the presence of a functional J-domain. The amount of DnaJC15 expressed in the cell was directly proportional to the sensitivity of cells. Our analysis indicates that the differential cellular phenotype displayed by human mitochondrial J-proteins is independent of their activity and association with Magmas at the translocation channel.In eukaryotic cells mitochondria form an essential organelle that plays a central role in cancer, apoptosis, and cytotoxic responses and maintains the overall metabolic homeostasis within the cell (1, 2). More than 98% of the human mitochondrial protein pool is nuclear-encoded and transported into the mitochondria through highly complex import machinery spanning the outer membrane, inner membrane, and the intermembrane space (2, 3). At the inner membrane, TIM23 complex forms the sole gateway for translocation of precursor proteins into the matrix, which accounts for ϳ60% of the total imported proteins (4, 5). The TIM23 complex comprises of two components: membrane-embedded Tim23 core channel and the motor component. Although the initial membrane potential dependent translocation is mediated by the Tim23-Tim17 channel, it is the overall activity of the import motor, which determines the translocation process (3, 4, 6 -10). The import motor contains mtHsp70 as its core, whose function is orchestrated by J-proteins (7,(11)(12)(13). The ADP/ATP states of Hsp70 regulate its interactions with client proteins (14, 15). However, the basal ATPase activity of Hsp70 is not sufficient to drive the reactions efficiently and, thus, requires J-proteins as cofactors ...

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Section: From the Department Of Biochemistry Indian Institute Of Scimentioning

confidence: 99%

Functional Diversity of Human Mitochondrial J-proteins Is Independent of Their Association with the Inner Membrane Presequence Translocase

Sinha

Srivastava

D’Silva

2016

Journal of Biological Chemistry

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“…Owing to distinct compartmentalization into an outer and inner membrane, mitochondria have evolved an efficient system for recognition and transport of precursor proteins across membranes. Import of nuclear encoded proteins into the mitochondrial membranes is a multistep process involving machinery of cytosol, mitochondrial membranes and mitochondrial matrix ( 6 – 10 ). As a first step in the translocation process, the cytosolic facing receptors recognize the mitochondrial targeting sequence of a precursor protein and transfer them to the protein complex of the outer membrane, where Tom40 forms a pore and allows passage of the precursor protein through the membrane ( 6 , 8 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

“…Import of nuclear encoded proteins into the mitochondrial membranes is a multistep process involving machinery of cytosol, mitochondrial membranes and mitochondrial matrix ( 6 – 10 ). As a first step in the translocation process, the cytosolic facing receptors recognize the mitochondrial targeting sequence of a precursor protein and transfer them to the protein complex of the outer membrane, where Tom40 forms a pore and allows passage of the precursor protein through the membrane ( 6 , 8 , 10 ). After passage through TOM complex, a major portion of precursor proteins are targeted into mitochondrial matrix; and this process is mediated by presequence translocase (TIM23 complex) of the inner membrane ( 7 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

Role of Magmas in protein transport and human mitochondria biogenesis

Sinha

Joshi

Chittoor

et al. 2010

Human Molecular Genetics

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Magmas, a conserved mammalian protein essential for eukaryotic development, is overexpressed in prostate carcinomas and cells exposed to granulocyte-macrophage colony-stimulating factor (GM-CSF). Reduced Magmas expression resulted in decreased proliferative rates in cultured cells. However, the cellular function of Magmas is still elusive. In this report, we have showed that human Magmas is an ortholog of Saccharomyces cerevisiae Pam16 having similar functions and is critical for protein translocation across mitochondrial inner membrane. Human Magmas shows a complete growth complementation of Δpam16 yeast cells at all temperatures. On the basis of our analysis, we report that Magmas localizes into mitochondria and is peripherally associated with inner mitochondrial membrane in yeast and humans. Magmas forms a stable subcomplex with J-protein Pam18 or DnaJC19 through its C-terminal region and is tethered to TIM23 complex of yeast and humans. Importantly, amino acid alterations in Magmas leads to reduced stability of the subcomplex with Pam18 that results in temperature sensitivity and in vivo protein translocation defects in yeast cells. These observations highlight the central role of Magmas in protein import and mitochondria biogenesis. In humans, absence of a functional DnaJC19 leads to dilated cardiac myophathic syndrome (DCM), a genetic disorder with characteristic features of cardiac myophathy and neurodegeneration. We propose that the mutations resulting in decreased stability of functional Magmas:DnaJC19 subcomplex at human TIM23 channel leads to impaired protein import and cellular respiration in DCM patients. Together, we propose a model showing how Magmas:DnaJC19 subcomplex is associated with TIM23 complex and thus regulates mitochondrial import process.

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“…So far two cases of tRNA import were independently described. The mechanism of tRK1 delivery into yeast mitochondria was studied in details and involved several targeting factors (Enolase-2 as an RNA chaperone and the cytosolic precursor of mitochondrial lysyl-tRNA synthetase pre-Msk1p) and the TOM/TIM translocators (Entelis et al 2006;Kamenski et al 2007b;Kolesnikova et al 2010;Tarassov et al 1995), issues recently reviewed elsewhere (Rubio and Hopper 2011;Salinas et al 2008;Schneider 2011). This cytosolic tRNA was partially found in the mitochondrial compartment of the cell in 1979 (Martin et al 1979), while the second tRNA Lys RNA Lys UUU , tRK2 resided only in the cytosol.…”

Section: Yeastmentioning

confidence: 99%

Translation in Mitochondria and Other Organelles

Duchêne¹

2013

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Directed import of macromolecules into mitochondria

Cited by 4 publications

References 99 publications

Functional Diversity of Human Mitochondrial J-proteins Is Independent of Their Association with the Inner Membrane Presequence Translocase

Functional Diversity of Human Mitochondrial J-proteins Is Independent of Their Association with the Inner Membrane Presequence Translocase

Role of Magmas in protein transport and human mitochondria biogenesis

Translation in Mitochondria and Other Organelles

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