Identification of a 66 KDa protein associated with yeast mitochondrial ATP synthase as heat shock protein hsp60

Gray, Robyn Elizabeth; Grasso, David G.; Maxwell, Ronald J.; Finnegan, Patrick M.; Nagley, Phillip; Devenish, Rodney J.

doi:10.1016/0014-5793(90)81024-i

Cited by 23 publications

(10 citation statements)

References 11 publications

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“…The F o F 1 ATP synthase ␣ subunit of complex V plays a critical role in the electron transport chain. In addition, it was reported to interact with a Hsp60 chaperone and reduce aggregate formation (40). We found that inhibition of SirT3 led to the accumulation of the F o F 1 ATP synthase ␣ subunit in the insoluble fraction, while its level decreased in the soluble fraction (Fig.…”

Section: Resultsmentioning

confidence: 69%

SirT3 Regulates the Mitochondrial Unfolded Protein Response

Papa

Germain

2014

Molecular and Cellular Biology

243

213

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The mitochondria of cancer cells are characterized by elevated oxidative stress caused by reactive oxygen species (ROS). Such an elevation in ROS levels contributes to mitochondrial reprogramming and malignant transformation. However, high levels of ROS can cause irreversible damage to proteins, leading to their misfolding, mitochondrial stress, and ultimately cell death. Therefore, mechanisms to overcome mitochondrial stress are needed. The unfolded protein response (UPR) triggered by accumulation of misfolded proteins in the mitochondria (UPR mt ) has been reported recently. So far, the UPR mt has been reported to involve the activation of CHOP and estrogen receptor alpha (ER␣). The current study describes a novel role of the mitochondrial deacetylase SirT3 in the UPR mt . Our data reveal that SirT3 acts to orchestrate two pathways, the antioxidant machinery and mitophagy. Inhibition of SirT3 in cells undergoing proteotoxic stress severely impairs the mitochondrial network and results in cellular death. These observations suggest that SirT3 acts to sort moderately stressed from irreversibly damaged organelles. Since SirT3 is reported to act as a tumor suppressor during transformation, our findings reveal a dual role of SirT3. This novel role of SirT3 in established tumors represents an essential mechanism of adaptation of cancer cells to proteotoxic and mitochondrial stress. Mitochondrial reprogramming associated with elevated reactive oxygen species (ROS) levels is a hallmark of cancers. Altered mitochondrial metabolism and ROS, both required during oncogenic transformation (1-4), are regulated by the mitochondrial deacetylase SirT3 (5-7). Reduction in SirT3 levels and the resulting elevated ROS levels have been directly linked to the switch to glycolysis, known as the Warburg effect (8). While ROS are required for glucose metabolism and metastasis in triple-negative breast cancers (9), decreased SirT3 levels concomitant with high ROS levels are frequently observed in all breast cancers (8). Based on these findings, SirT3 is considered a tumor suppressor (5,8).SirT3 regulates the activity of magnesium superoxide dismutase (MnSOD), which detoxifies superoxide to hydrogen peroxide (5,7,(10)(11)(12)(13)(14). Moreover, SirT3 has been linked to augmented transcription of MnSOD and catalase, both known targets of the transcription factor FOXO3A (15). The SirT3-dependent deacetylation of FOXO3A promotes both its nuclear translocation and its transcriptional activity (16,17). Therefore, mechanistically, the reduction of SirT3 levels leads to an elevation in ROS levels by compromising the mitochondrial antioxidant machinery.Mitochondria are the main source of ROS production (18). However, they are also the main targets of oxidative stress. Excessive ROS induce oxidative damage to DNA, lipids, and proteins, leading to their misfolding and aggregation in the mitochondria. Upon accumulation of misfolded and aggregated proteins in the mitochondria, cells mount the unfolded protein response (UPR mt ), a mitochondrial-to nu...

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Section: Resultsmentioning

confidence: 69%

SirT3 Regulates the Mitochondrial Unfolded Protein Response

Papa

Germain

2014

Molecular and Cellular Biology

243

213

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“…Likewise, four subunits were identified in a lane for complex V; five subunits in a lane for complex III 2 ; and seven subunits derived from complex I and complex III in a lane for supercomplex I+III 2 . Heat shock protein 60-like proteins were also detected in lanes for complex V in the mitochondria from both thermogenic plants, as reported previously in yeast mitochondria [25]. Complex II could be characterized by Fp subunits and, when available, iron-sulfur subunit (Ip subunit) on the gels.…”

Section: Resultssupporting

confidence: 80%

Different molecular bases underlie the mitochondrial respiratory activity in the homoeothermic spadices of Symplocarpus renifolius and the transiently thermogenic appendices of Arum maculatum

Kakizaki

Moore

Ito

2012

Biochemical Journal

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Symplocarpus renifolius and Arum maculatum are known to produce significant heat during the course of their floral development, but they use different regulatory mechanisms, i.e. homoeothermic compared with transient thermogenesis. To further clarify the molecular basis of species-specific thermogenesis in plants, in the present study we have analysed the native structures and expression patterns of the mitochondrial respiratory components in S. renifolius and A. maculatum. Our comparative analysis using Blue native PAGE combined with nano LC (liquid chromatography)-MS/MS (tandem MS) has revealed that the constituents of the respiratory complexes in both plants were basically similar, but that several mitochondrial components appeared to be differently expressed in their thermogenic organs. Namely, complex II in S. renifolius was detected as a 340 kDa product, suggesting an oligomeric or supramolecular structure in vivo. Moreover, the expression of an external NAD(P)H dehydrogenase was found to be higher in A. maculatum than in S. renifolius, whereas an internal NAD(P)H dehydrogenase was expressed at a similar level in both species. Alternative oxidase was detected as smear-like signals that were elongated on the first dimension with a peak at around 200 kDa in both species. The significance and implication of these data are discussed in terms of thermoregulation in plants.

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“…Biogenesis of F 1 requires the general chaperone Hsp60p (14) and at least three factors, Atp11p, Atp12p, and Fmc1p (15)(16)(17). Atp11p and Atp12p function as molecular chaperones that probably stabilize unassembled ␣ and ␤ subunits by shielding their hydrophobic surfaces (16,18).…”

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confidence: 99%

Atp10p Assists Assembly of Atp6p into the F0 Unit of the Yeast Mitochondrial ATPase

Tzagoloff

Barrientos

Neupert

et al. 2004

Journal of Biological Chemistry

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The F 0 F 1 -ATPase complex of yeast mitochondria contains three mitochondrial and at least 17 nuclear gene products. The coordinate assembly of mitochondrial and cytosolic translation products relies on chaperones and specific factors that stabilize the pools of some unassembled subunits. Atp10p was identified as a mitochondrial inner membrane component necessary for the biogenesis of the hydrophobic F 0 sector of the ATPase. Here we show that, following its synthesis on mitochondrial ribosomes, subunit 6 of the ATPase (Atp6p) can be cross-linked to Atp10p. This interaction is required for the integration of Atp6p into a partially assembled subcomplex of the ATPase. Pulse labeling and chase of mitochondrial translation products in vivo indicate that Atp6p is less stable and more rapidly degraded in an atp10 null mutant than in wild type. Based on these observations, we propose Atp10p to be an Atp6p-specific chaperone that facilitates the incorporation of Atp6p into an intermediate subcomplex of ATPase subunits.

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Identification of a 66 KDa protein associated with yeast mitochondrial ATP synthase as heat shock protein hsp60

Cited by 23 publications

References 11 publications

SirT3 Regulates the Mitochondrial Unfolded Protein Response

SirT3 Regulates the Mitochondrial Unfolded Protein Response

Different molecular bases underlie the mitochondrial respiratory activity in the homoeothermic spadices of Symplocarpus renifolius and the transiently thermogenic appendices of Arum maculatum

Atp10p Assists Assembly of Atp6p into the F0 Unit of the Yeast Mitochondrial ATPase

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