Genetic analysis of mitochondrial protein misfolding in Drosophila melanogaster

Castro, Inês Pimenta de; Costa, AC; Lam, David; Tufi, Roberta; Fedele, Valentina; Moisoi, Nicoleta; Dinsdale, David; Deas, Emma; Loh, Sh H. Y.; Martins, L. Miguel

doi:10.1038/cdd.2012.5

Cited by 111 publications

(129 citation statements)

References 30 publications

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“…Considering the proposed functions of i-AAA in mitochondrial proteostasis, we assessed the amount of HSP60, a marker for the unfolded protein response in mitochondria (UPR mt ). 40,41 Western blot analysis showed that HSP60 was more abundant in dYME1L del flies compared with that in wild-type flies throughout adulthood (Figure 6a), supporting the idea that mitochondrial i-AAA protease deficiency disrupts mitochondrial protein homeostasis, leading to an elevated mitochondrial unfolded protein stress.…”

Section: Resultssupporting

confidence: 57%

“…Indeed many mitochondrial mutations perturbing mitochondrial proteostasis compromise complex I. 41,56 Flies carrying the Drosophila Sicily mutation that disrupts complex I assembly also display reduced complex I activity, elevated ROS level and retinal degeneration. 56 However, there is no detectable apoptosis in the Sicily mutant, suggesting the existence of caspase-independent cell death and the insufficiency for ROS alone to elicit apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Liu

Daniels

et al. 2015

Cell Death Differ

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Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L del ). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1L del flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1L del flies had reduced complex I (NADH/ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency.

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Section: Resultssupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Liu

Daniels

et al. 2015

Cell Death Differ

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“…More specifically, mitochondrial proteotoxic stress was shown to induce mitophagy in Drosophila melanogaster (29); however, the mechanism remains unknown.…”

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confidence: 99%

SirT3 Regulates the Mitochondrial Unfolded Protein Response

Papa

Germain

2014

Molecular and Cellular Biology

237

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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“…Similar to p62, Ref(2)P accumulates with ubiquitin-containing protein aggregates in the brain of autophagy-deficient and neurodegenerative mutants of Drosophila (39,44). Ref (2)P is involved in maintenance of the viable mitochondria pool by acting downstream of Pink1 and Parkin, where Ref(2)P recycles excessive unfolded proteins via autophagy (69). This indicates a role for Ref (2)P as an autophagy receptor, similar to mammalian p62.…”

Section: Discussionmentioning

confidence: 77%