Mitochondrial Protein Quality Control by the Proteasome Involves Ubiquitination and the Protease Omi

We report here that blocking the activity of the 26 S proteasome results in drastic changes in the morphology of the mitochondria and accumulation of intermembrane space (IMS) proteins. Using endonuclease G (endoG) as a model IMS protein, we found that accumulation of wild-type but to a greater extent mutant endoG leads to changes in the morphology of the mitochondria similar to those observed following proteasomal inhibition. Further, we show that wild-type but to a greater extent mutant endoG is a substrate for ubiquitination, suggesting the presence of a protein quality control. Conversely, we also report that wild-type but not mutant endoG is a substrate for the mitochondrial protease Omi but only upon inhibition of the proteasome. These findings suggest that although elimination of mutant IMS proteins is strictly dependent on ubiquitination, elimination of excess or spontaneously misfolded wild-type IMS proteins is monitored by ubiquitination and as a second checkpoint by Omi cleavage when the proteasome function is deficient. One implication of our finding is that in the context of attenuated proteasomal function, accumulation of IMS proteins would contribute to the collapse of the mitochondrial network such as that observed in neurodegenerative diseases. Another implication is that such collapse could be accelerated either by mutations in IMS proteins or by mutations in Omi itself. We report here that blocking the activity of the 26 S proteasome results in drastic changes in the morphology of the mitochondria and accumulation of intermembrane space (IMS) proteins. Using endonuclease G (endoG) as a model IMS protein, we found that accumulation of wild-type but to a greater extent mutant endoG leads to changes in the morphology of the mitochondria similar to those observed following proteasomal inhibition. Further, we show that wild-type but to a greater extent mutant endoG is a substrate for ubiquitination, suggesting the presence of a protein quality control. Conversely, we also report that wild-type but not mutant endoG is a substrate for the mitochondrial protease Omi but only upon inhibition of the proteasome. These findings suggest that although elimination of mutant IMS proteins is strictly dependent on ubiquitination, elimination of excess or spontaneously misfolded wild-type IMS proteins is monitored by ubiquitination and as a second checkpoint by Omi cleavage when the proteasome function is deficient. One implication of our finding is that in the context of attenuated proteasomal function, accumulation of IMS proteins would contribute to the collapse of the mitochondrial network such as that observed in neurodegenerative diseases. Another implication is that such collapse could be accelerated either by mutations in IMS proteins or by mutations in Omi itself. The elimination of misfolded proteins represents an important mechanism for the maintenance of cellular viability. Such protein quality controls (PQC) 4The abbreviations used are: PQC, protein quality control(s); IMS, intermembrane space; endoG, endonuclease G; ER, endoplasmic reticulum; PBS, phosphate-buffered saline; HA, hemagglutinin; GFP, green fluorescent protein; MLS, mitochondrial localization signal; hsp, heat shock protein; LLnL, N-acetyl-l-leucyl-l-leucyl-l-norleucinal; PINK, PTEN-induced putative kinase 1. 4The abbreviations used are: PQC, protein quality control(s); IMS, intermembrane space; endoG, endonuclease G; ER, endoplasmic reticulum; PBS, phosphate-buffered saline; HA, hemagglutinin; GFP, green fluorescent protein; MLS, mitochondrial localization signal; hsp, heat shock protein; LLnL, N-acetyl-l-leucyl-l-leucyl-l-norleucinal; PINK, PTEN-induced putative kinase 1. involve the binding of a chaperone to the misfolded protein and its presentation to the ubiquitin-dependent proteasome degradation pathway (1Kostova Z. Wolf D.H. EMBO J. 2003; 22: 2309-2317Crossref PubMed Scopus (361) Google Scholar, 2Goldberg A.L. Nature. 2003; 426: 895-899Crossref PubMed Scopus (1648) Google Scholar). Linkage of ubiquitin to a protein is a highly organized process involving the sequential action of a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-ligase (E3) (3Ciechanover A. Cell Death Differ. 2005; 12: 1178-1190Crossref PubMed Scopus (267) Google Scholar). Most of the regulation of the ubiquitination pathway occurs at the level of the ubiquitin ligase. This enzymatic results in the of a of a of that on of ubiquitin as a for degradation by the 26 S proteasome. The S of the proteasome of a that is by S The in the and in the or in the endoplasmic A. EMBO J. PubMed Scopus Google Scholar, PubMed Scopus Google in the of the heat shock protein that in ubiquitin A.L. Nature. 2003; 426: 895-899Crossref PubMed Scopus (1648) Google Scholar). similar in the 2005; PubMed Scopus Google Scholar). also found to the of proteins in the of the endoplasmic a that at proteins that the to be to the pathway (1Kostova Z. Wolf D.H. EMBO J. 2003; 22: 2309-2317Crossref PubMed Scopus (361) Google Scholar, Nature. 2003; 426: PubMed Scopus Google Scholar, Cell 2005; PubMed Scopus Google Scholar). found that misfolded proteins in the by such as and the for ubiquitin-dependent degradation J. Wolf D.H. Nature. PubMed Scopus Google Scholar). Further, the of the ubiquitin to be for the process J. Wolf D.H. Nature. PubMed Scopus Google Scholar, J. Wolf D.H. Cell PubMed Scopus Google and a of the the to proteins as Wolf D.H. PubMed Google Scholar). The that inhibition of the proteasome activity results in the accumulation of misfolded proteins on the of the in the mitochondria also but PQC, elimination of misfolded proteins the mitochondria not ubiquitination but the action of the PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). The is a that the and the The and the mitochondrial The space the and is to as the intermembrane space (IMS) and proteins. Most IMS proteins for in the of upon the mitochondria and and the of the and to proteins the and proteins the J. 2005; PubMed Scopus Google Scholar). only protein of the IMS the quality of report here that inhibition of the proteasome leads to the accumulation of IMS proteins in the mitochondria and that a ubiquitin-dependent protein quality the of mutant IMS proteins. we found that accumulation of IMS proteins the of the mitochondria to that observed upon inhibition of the proteasome. our results suggest a of the ubiquitin pathway in the maintenance of the and in and and mutant in the the as by the and protein in and in of by at for at and the protein of the protein as A. 2005; PubMed Scopus Google and for proteins by to and the following of to to and by in a at a of and and in for at The for at blocking of to the for at and or used as at a of and for at of for and in and on in on a a and a and at of the 26 S the of IMS and the of the ubiquitin pathway in the of IMS we the proteasome and the of such on by We found that the of when also the activity of the of the proteasome in a proteasome also to the accumulation of and to the of the in a to of intermembrane space protein, endoG, also in the presence or of proteasome We found that as observed the of endoG upon proteasome and that the also a The observed IMS Omi and the by A. J. J. PubMed Scopus Google inhibition of the proteasome leads to the of IMS proteins the of proteasome inhibition on the mitochondria on the of IMS proteins This that upon proteasome the mitochondria when mitochondria in and These results the that upon inhibition of the proteins in the the and the accumulation of IMS proteins observed by Further, results the that a to the of excess or misfolded mitochondrial proteins. the accumulation of mitochondrial proteins and the of mitochondria also following an of the chaperone D.H. PubMed Scopus Google the of a PQC, wild-type G or a mutant of endonuclease G in the of proteasome We found that accumulation of wild-type endonuclease G to a mitochondrial in of the in of the a similar to those observed endoG in the presence of proteasome mutant endoG the of to of We the of proteasome on the of mutant We found that upon proteasomal of show The accumulation of mutant endoG in the mitochondria of the mitochondria and endoG to the and to an in the of endoG in the mitochondria but not in the We the of accumulation of mutant endoG on the morphology of the mitochondria by We found that of also to the accumulation of mitochondria similar to those observed upon proteasome the of the mitochondria not as as the observed following proteasome suggesting that although accumulation of IMS proteins such as endoG is to contribute to the of upon proteasomal of proteins also contribute to inhibition of to to the accumulation of mitochondrial proteins the and D.H. PubMed Scopus Google the of of the mitochondria localization We found that the and and as not to the mitochondria a and Further, of the mitochondrial the of to the that its level to those of This that of mutant endoG not to protein and that in the mitochondria is for the and of the mitochondria to be results suggest that the activity of the proteasome is to the accumulation of proteins in the IMS and that upon inhibition of the such accumulation to the collapse of the by a to the of a for IMS we wild-type and mutant endoG for We that a is such the ubiquitination of mutant endoG be drastic wild-type endoG such not only the presence of excess and proteins but also the elimination of misfolded proteins. We found that although wild-type endoG a substrate for ubiquitination, the ubiquitination of mutant endoG when wild-type endoG The The ubiquitination of mutant wild-type of endoG that the ubiquitination is not to but is the presence of a of IMS proteins that misfolded protein quality and Omi in the regulation of the and the proteasome and the to the and the proteasome and the to the and the proteasome The of and Omi by and Omi the and the proteasome The of by at the ubiquitination in the to in the or as is the in the endoplasmic and and ubiquitination J. Wolf D.H. Nature. PubMed Scopus Google Scholar, Wolf D.H. PubMed Google Scholar). the mitochondrial localization of mutant endoG and the level of its ubiquitination We found that of the not the ubiquitination of mutant endoG suggesting that the ubiquitination not the IMS and not involve that misfolded IMS proteins and in the to the our suggest that the accumulation of IMS proteins in the mitochondria following proteasome inhibition is to the of the elimination of the misfolded IMS proteins and in the endoG of wild-type and mutant endoG that wild-type but not mutant endoG as a in to proteasome inhibition suggesting that a protease be following proteasome inhibition. the of the mitochondrial protease to the intermembrane space endoG, to following by kinase in to a of proteasome inhibition J. Cell PubMed Scopus Google Scholar). We Omi be for the cleavage of endoG following We found that of Omi the level of endoG, suggesting that the of the represents a cleavage that the but that Omi is to endoG The of cleavage wild-type endoG of cleavage observed when wild-type endoG This that although excess or spontaneously misfolded wild-type endoG be for degradation by ubiquitination, when the proteasome function is cleavage by Omi represents a second checkpoint to accumulation in the elimination of mutant endoG is dependent on the ubiquitin we the presence of a that the of proteins to the IMS of the This to to the the IMS on the that of the mitochondrial not the ubiquitination of mutant One is that and by ubiquitin is by in the is by that would in its of the of D.H. PubMed Scopus Google that the of mitochondrial is and endoG ubiquitination accumulation of mitochondrial proteins following inhibition of the proteasome we here is also the by D.H. PubMed Scopus Google similar findings the findings here and the by D.H. PubMed Scopus Google an important for the ubiquitin pathway in the of mitochondrial protein the of the of Omi following proteasome inhibition J. Cell PubMed Scopus Google Scholar). proteins to be of Omi following its the mitochondria the mitochondrial of Omi following proteasomal We report here that endoG is a substrate for Omi cleavage following proteasome inhibition. These results not only endoG as substrate for the mitochondrial function of Omi but also that in endoG endoG to such findings function of the proteasome to the of neurodegenerative the implication of our findings is that in the proteasome function is accumulation of mitochondrial proteins a collapse of the mitochondrial second implication is that such a collapse be accelerated by the of in IMS proteins such as endoG such at mitochondrial and to the implication is that in Omi as in also contribute to the accelerated collapse of the mitochondrial network by the Omi the that our findings and that of is that mitochondrial proteins by the ubiquitin-dependent protein quality to the at the endoplasmic Further, the proteasome also the activity of the protease an important second checkpoint to the accumulation of mitochondrial proteins. The that Omi and A. J. J. PubMed Scopus Google in IMS proteins in neurodegenerative and the in proteasome and such mutations accelerated of the our findings of those a and The elimination of misfolded proteins represents an important mechanism for the maintenance of cellular viability. Such protein quality controls (PQC) 4The abbreviations used are: PQC, protein quality control(s); IMS, intermembrane space; endoG, endonuclease G; ER, endoplasmic reticulum; PBS, phosphate-buffered saline; HA, hemagglutinin; GFP, green fluorescent protein; MLS, mitochondrial localization signal; hsp, heat shock protein; LLnL, N-acetyl-l-leucyl-l-leucyl-l-norleucinal; PINK, PTEN-induced putative kinase 1. 4The abbreviations used are: PQC, protein quality control(s); IMS, intermembrane space; endoG, endonuclease G; ER, endoplasmic reticulum; PBS, phosphate-buffered saline; HA, hemagglutinin; GFP, green fluorescent protein; MLS, mitochondrial localization signal; hsp, heat shock protein; LLnL, N-acetyl-l-leucyl-l-leucyl-l-norleucinal; PINK, PTEN-induced putative kinase 1. involve the binding of a chaperone to the misfolded protein and its presentation to the ubiquitin-dependent proteasome degradation pathway (1Kostova Z. Wolf D.H. EMBO J. 2003; 22: 2309-2317Crossref PubMed Scopus (361) Google Scholar, 2Goldberg A.L. Nature. 2003; 426: 895-899Crossref PubMed Scopus (1648) Google Scholar). Linkage of ubiquitin to a protein is a highly organized process involving the sequential action of a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-ligase (E3) (3Ciechanover A. Cell Death Differ. 2005; 12: 1178-1190Crossref PubMed Scopus (267) Google Scholar). Most of the regulation of the ubiquitination pathway occurs at the level of the ubiquitin ligase. This enzymatic results in the of a of a of that on of ubiquitin as a for degradation by the 26 S proteasome. The S of the proteasome of a that is by S The in the and in the or in the endoplasmic A. EMBO J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). in the of the heat shock protein that in ubiquitin A.L. Nature. 2003; 426: 895-899Crossref PubMed Scopus (1648) Google Scholar). similar in the 2005; PubMed Scopus Google Scholar). also found to the of proteins in the of the endoplasmic a that at proteins that the to be to the pathway (1Kostova Z. Wolf D.H. EMBO J. 2003; 22: 2309-2317Crossref PubMed Scopus (361) Google Scholar, Nature. 2003; 426: PubMed Scopus Google Scholar, Cell 2005; PubMed Scopus Google Scholar). found that misfolded proteins in the by such as and the for ubiquitin-dependent degradation J. Wolf D.H. Nature. PubMed Scopus Google Scholar). Further, the of the ubiquitin to be for the process J. Wolf D.H. Nature. PubMed Scopus Google Scholar, J. Wolf D.H. Cell PubMed Scopus Google and a of the the to proteins as Wolf D.H. PubMed Google Scholar). The that inhibition of the proteasome activity results in the accumulation of misfolded proteins on the of the in the mitochondria also but PQC, elimination of misfolded proteins the mitochondria not ubiquitination but the action of the PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). The is a that the and the The and the mitochondrial The space the and is to as the intermembrane space (IMS) and proteins. Most IMS proteins for in the of upon the mitochondria and and the of the and to proteins the and proteins the J. 2005; PubMed Scopus Google Scholar). only protein of the IMS the quality of proteins. We report here that inhibition of the proteasome leads to the accumulation of IMS proteins in the mitochondria and that a ubiquitin-dependent protein quality the of mutant IMS proteins. we found that accumulation of IMS proteins the of the mitochondria to that observed upon inhibition of the proteasome. our results suggest a of the ubiquitin pathway in the maintenance of the and in and and mutant in the the as by the and protein in and in of by at for at and the protein of the protein as A. 2005; PubMed Scopus Google and for proteins by to and the following of to to and by in a at a of and and in for at The for at blocking of to the for at and or used as at a of and for at of for and in and on in on a a and a and at Cell and in and and mutant in the the as by the and protein in and in of by at for at and the protein of the protein as A. 2005; PubMed Scopus Google and for proteins by to and the following of to to and by in a at a of and and in for at The for at blocking of to the for at and or used as at a of and for at of for and in and on in on a a and a and at of the 26 S the of IMS and the of the ubiquitin pathway in the of IMS we the proteasome and the of such on by We found that the of when also the activity of the of the proteasome in a proteasome also to the accumulation of and to the of the in a to of intermembrane space protein, endoG, also in the presence or of proteasome We found that as observed the of endoG upon proteasome and that the also a The observed IMS Omi and the by A. J. J. PubMed Scopus Google inhibition of the proteasome leads to the of IMS proteins the of proteasome inhibition on the mitochondria on the of IMS proteins This that upon proteasome the mitochondria when mitochondria in and These results the that upon inhibition of the proteins in the the and the accumulation of IMS proteins observed by Further, results the that a to the of excess or misfolded mitochondrial proteins. the accumulation of mitochondrial proteins and the of mitochondria also following an of the chaperone D.H. PubMed Scopus Google the of a PQC, wild-type G or a mutant of endonuclease G in the of proteasome We found that accumulation of wild-type endonuclease G to a mitochondrial in of the in of the a similar to those observed endoG in the presence of proteasome mutant endoG the of to of We the of proteasome on the of mutant We found that upon proteasomal of show The accumulation of mutant endoG in the mitochondria of the mitochondria and endoG to the and to an in the of endoG in the mitochondria but not in the We the of accumulation of mutant endoG on the morphology of the mitochondria by We found that of also to the accumulation of mitochondria similar to those observed upon proteasome the of the mitochondria not as as the observed following proteasome suggesting that although accumulation of IMS proteins such as endoG is to contribute to the of upon proteasomal of proteins also contribute to inhibition of to to the accumulation of mitochondrial proteins the and D.H. PubMed Scopus Google the of of the mitochondria localization We found that the and and as not to the mitochondria a and Further, of the mitochondrial the of to the that its level to those of This that of mutant endoG not to protein and that in the mitochondria is for the and of the mitochondria to be results suggest that the activity of the proteasome is to the accumulation of proteins in the IMS and that upon inhibition of the such accumulation to the collapse of the by a to the of a for IMS we wild-type and mutant endoG for We that a is such the ubiquitination of mutant endoG be drastic wild-type endoG such not only the presence of excess and proteins but also the elimination of misfolded proteins. We found that although wild-type endoG a substrate for ubiquitination, the ubiquitination of mutant endoG when wild-type endoG The The ubiquitination of mutant wild-type of endoG that the ubiquitination is not to but is the presence of a of IMS proteins that misfolded at the ubiquitination in the to in the or as is the in the endoplasmic and and ubiquitination J. Wolf D.H. Nature. PubMed Scopus Google Scholar, Wolf D.H. PubMed Google Scholar). the mitochondrial localization of mutant endoG and the level of its ubiquitination We found that of the not the ubiquitination of mutant endoG suggesting that the ubiquitination not the IMS and not involve that misfolded IMS proteins and in the to the our suggest that the accumulation of IMS proteins in the mitochondria following proteasome inhibition is to the of the elimination of the misfolded IMS proteins and in the endoG of wild-type and mutant endoG that wild-type but not mutant endoG as a in to proteasome inhibition suggesting that a protease be following proteasome inhibition. the of the mitochondrial protease to the intermembrane space endoG, to following by kinase in to a of proteasome inhibition J. Cell PubMed Scopus Google Scholar). We Omi be for the cleavage of endoG following We found that of Omi the level of endoG, suggesting that the of the represents a cleavage that the but that Omi is to endoG The of cleavage wild-type endoG of cleavage observed when wild-type endoG This that although excess or spontaneously misfolded wild-type endoG be for degradation by ubiquitination, when the proteasome function is cleavage by Omi represents a second checkpoint to accumulation in the elimination of mutant endoG is dependent on the ubiquitin of the 26 S the of IMS and the of the ubiquitin pathway in the of IMS we the proteasome and the of such on by We found that the of when also the activity of the of the proteasome in a proteasome also to the accumulation of and to the of the in a to of intermembrane space protein, endoG, also in the presence or of proteasome We found that as observed the of endoG upon proteasome and that the also a The observed IMS Omi and the by A. J. J. PubMed Scopus Google inhibition of the proteasome leads to the of IMS proteins We the of proteasome inhibition on the mitochondria on the of IMS proteins This that upon proteasome the mitochondria when mitochondria in and These results the that upon inhibition of the proteins in the the and the accumulation of IMS proteins observed by Further, results the that a to the of excess or misfolded mitochondrial proteins. the accumulation of mitochondrial proteins and the of mitochondria also following an of the chaperone D.H. PubMed Scopus Google Scholar). the of a PQC, wild-type G or a mutant of endonuclease G in the of proteasome We found that accumulation of wild-type endonuclease G to a mitochondrial in of the in of the a similar to those observed endoG in the presence of proteasome mutant endoG the of to of We the of proteasome on the of mutant We found that upon proteasomal of show The accumulation of mutant endoG in the mitochondria of the mitochondria and endoG to the and to an in the of endoG in the mitochondria but not in the We the of accumulation of mutant endoG on the morphology of the mitochondria by We found that of also to the accumulation of mitochondria similar to those observed upon proteasome the of the mitochondria not as as the observed following proteasome suggesting that although accumulation of IMS proteins such as endoG is to contribute to the of upon proteasomal of proteins also contribute to inhibition of to to the accumulation of mitochondrial proteins the and D.H. PubMed Scopus Google Scholar). We the of of the mitochondria localization We found that the and and as not to the mitochondria a and Further, of the mitochondrial the of to the that its level to those of This that of mutant endoG not to protein and that in the mitochondria is for the and of the mitochondria to be results suggest that the activity of the proteasome is to the accumulation of proteins in the IMS and that upon inhibition of the such accumulation to the collapse of the IMS by a to the of a for IMS we wild-type and mutant endoG for We that a is such the ubiquitination of mutant endoG be drastic wild-type endoG such not only the presence of excess and proteins but also the elimination of misfolded proteins. We found that although wild-type endoG a substrate for ubiquitination, the ubiquitination of mutant endoG when wild-type endoG The The ubiquitination of mutant wild-type of endoG that the ubiquitination is not to but is the presence of a of IMS proteins that misfolded proteins. We at the ubiquitination in the to in the or as is the in the endoplasmic and and ubiquitination J. Wolf D.H. Nature. PubMed Scopus Google Scholar, Wolf D.H. PubMed Google Scholar). the mitochondrial localization of mutant endoG and the level of its ubiquitination We found that of the not the ubiquitination of mutant endoG suggesting that the ubiquitination not the IMS and not involve that misfolded IMS proteins and in the to the our suggest that the accumulation of IMS proteins in the mitochondria following proteasome inhibition is to the of the elimination of the misfolded IMS proteins and in the Omi endoG of wild-type and mutant endoG that wild-type but not mutant endoG as a in to proteasome inhibition suggesting that a protease be following proteasome inhibition. the of the mitochondrial protease to the intermembrane space endoG, to following by kinase in to a of proteasome inhibition J. Cell PubMed Scopus Google Scholar). We Omi be for the cleavage of endoG following We found that of Omi the level of endoG, suggesting that the of the represents a cleavage that the but that Omi is to endoG The of cleavage wild-type endoG of cleavage observed when wild-type endoG This that although excess or spontaneously misfolded wild-type endoG be for degradation by ubiquitination, when the proteasome function is cleavage by Omi represents a second checkpoint to accumulation in the elimination of mutant endoG is dependent on the ubiquitin we the presence of a that the of proteins to the IMS of the This to to the the IMS on the that of the mitochondrial not the ubiquitination of mutant One is that and by ubiquitin is by in the is by that would in its of the of D.H. PubMed Scopus Google that the of mitochondrial is and endoG ubiquitination accumulation of mitochondrial proteins following inhibition of the proteasome we here is also the by D.H. PubMed Scopus Google similar findings the findings here and the by D.H. PubMed Scopus Google an important for the ubiquitin pathway in the of mitochondrial protein the of the of Omi following proteasome inhibition J. Cell PubMed Scopus Google Scholar). proteins to be of Omi following its the mitochondria the mitochondrial of Omi following proteasomal We report here that endoG is a substrate for Omi cleavage following proteasome inhibition. These results not only endoG as substrate for the mitochondrial function of Omi but also that in endoG endoG to such findings function of the proteasome to the of neurodegenerative the implication of our findings is that in the proteasome function is accumulation of mitochondrial proteins a collapse of the mitochondrial second implication is that such a collapse be accelerated by the of in IMS proteins such as endoG such at mitochondrial and to the implication is that in Omi as in also contribute to the accelerated collapse of the mitochondrial network by the Omi the that our findings and that of is that mitochondrial proteins by the ubiquitin-dependent protein quality to the at the endoplasmic Further, the proteasome also the activity of the protease an important second checkpoint to the accumulation of mitochondrial proteins. The that Omi and A. J. J. PubMed Scopus Google in IMS proteins in neurodegenerative and the in proteasome and such mutations accelerated of the our findings of those a and we the presence of a that the of proteins to the IMS of the This to to the the IMS on the that of the mitochondrial not the ubiquitination of mutant One is that and by ubiquitin is by in the is by that would in its of the of D.H. PubMed Scopus Google that the of mitochondrial is and endoG ubiquitination The accumulation of mitochondrial proteins following inhibition of the proteasome we here is also the by D.H. PubMed Scopus Google similar findings the findings here and the by D.H. PubMed Scopus Google an important for the ubiquitin pathway in the of mitochondrial protein the of the of Omi following proteasome inhibition J. Cell PubMed Scopus Google Scholar). proteins to be of Omi following its the mitochondria the mitochondrial of Omi following proteasomal We report here that endoG is a substrate for Omi cleavage following proteasome inhibition. These results not only endoG as substrate for the mitochondrial function of Omi but also that in endoG endoG to such These findings function of the proteasome to the of neurodegenerative the implication of our findings is that in the proteasome function is accumulation of mitochondrial proteins a collapse of the mitochondrial second implication is that such a collapse be accelerated by the of in IMS proteins such as endoG such at mitochondrial and to the implication is that in Omi as in also contribute to the accelerated collapse of the mitochondrial network by the Omi the that our findings and that of is that mitochondrial proteins by the ubiquitin-dependent protein quality to the at the endoplasmic Further, the proteasome also the activity of the protease an important second checkpoint to the accumulation of mitochondrial proteins. The that Omi and A. J. J. PubMed Scopus Google in IMS proteins in neurodegenerative and the in proteasome and such mutations accelerated of the our findings of those a and by the at is the of and of