New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies

Ojala, Tiina; Polinati, Padmini P.; Manninen, Tuula; Hiippala, Anita; Rajantie, Jukka; Karikoski, Riitta; Suomalainen, Anu; Tyni, Tiina

doi:10.1038/pr.2012.92

Cited by 85 publications

(67 citation statements)

References 19 publications

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“…In contrast, a loss of function mutation in the J-domain of JC19 leads to a severe pathophysiological disorder, dilated cardiomyopathy and ataxia (DCM) 3 syndrome, that is characterized by cardiomyopathy and ataxia (24). It has been suggested that loss of subcomplex formation between JC19 and Magmas results in import defect and generation of characteristic DCM phenotypes (23,24,35).…”

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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“…The screen encompassed a total of 30,000 compounds dissolved in DMSO (supplemental Table S2). The strain in minimal glucose medium lacking uracil was aliquoted into 384-well pates (consisting of 24 columns) followed by compound addition with robotic pinning into the assay wells (column [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. For a negative control of cell growth, column 2 contained WT[Su9-URA3] strain with 1% DMSO.…”

Section: An In Vivo Screen To Identify Inhibitors Of Mitochondrial Prmentioning

confidence: 99%

“…Mutant DNAJC19, the homolog of Pam18, causes the dilated cardiomyopathy with ataxia syndrome (7). The human homolog of yeast Pam16, Magmas, is overexpressed in adenocarcinoma (8).…”

mentioning

confidence: 99%

Adaptation of a Genetic Screen Reveals an Inhibitor for Mitochondrial Protein Import Component Tim44

Miyata

Tang

Conti

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuDiverse protein import pathways into mitochondria use translocons on the outer membrane (TOM) and inner membrane (TIM). We adapted a genetic screen, based on Ura3 mistargeting from mitochondria to the cytosol, to identify small molecules that attenuated protein import. Small molecule mitochondrial import blockers of the Carla Koehler laboratory (MB)-10 inhibited import of substrates that require the TIM23 translocon. Mutational analysis coupled with molecular docking and molecular dynamics modeling revealed that MB-10 binds to a specific pocket in the C-terminal domain of Tim44 of the protein-associated motor (PAM) complex. This region was proposed to anchor Tim44 to the membrane, but biochemical studies with MB-10 show that this region is required for binding to the translocating precursor and binding to mtHsp70 in low ATP conditions. This study also supports a direct role for the PAM complex in the import of substrates that are laterally sorted to the inner membrane, as well as the mitochondrial matrix. Thus, MB-10 is the first small molecule modulator to attenuate PAM complex activity, likely through binding to the C-terminal region of Tim44.

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“…OPA3 (MIM #606580) mutations cause Costeff syndrome, characterized by early onset optic atrophy and neurological abnormalities including spasticity, extrapyramidal dysfunction, and cognitive deficits (Anikster et al 2001;Sheffer et al 1992). DNAJC19 (MIM #608977) mutations cause DCMA syndrome, characterized by dilated cardiomyopathy and ataxia (Davey et al 2006;Ojala et al 2012). Defects in TMEM70 (MIM #612418), involved in complex V of the electron transport chain, have been associated with cataracts, gastrointestinal dysfunction, and hypertonia (Jonckheere et al 2012).…”

Section: Introductionmentioning

confidence: 98%

The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations

et al. 2014

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The inborn errors of metabolism associated with 3-methylglutaconic aciduria are a diverse group of disorders characterized by the excretion of 3-methylglutaconic and 3-methylglutaric acids in the urine. Mutations in several genes have been identified in association with 3-methylglutaconic aciduria. We describe a patient of Saudi Arabian descent with 3-methylglutaconic aciduria, sensorineural hearing loss, encephalopathy, and Leigh-like pattern on MRI (MEGDEL syndrome), as well as developmental delay and developmental regression, bilateral optic nerve atrophy, microcephaly, and myoclonic epilepsy. The patient had an earlier age of onset of optic atrophy than previously described in other MEGDEL syndrome patients. Whole exome sequencing revealed two loss-of-function mutations in SERAC1 in trans: c.438delC (p.T147Rfs*22) and c.442C>T (p.R148X), confirmed by Sanger sequencing. One of these mutations is novel (c.438delC). This case contributes to refining the MEGDEL phenotype.

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New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies

Cited by 85 publications

References 19 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

Adaptation of a Genetic Screen Reveals an Inhibitor for Mitochondrial Protein Import Component Tim44

The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations

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