The loss of LRPPRC function induces the mitochondrial unfolded protein response

Köhler, Fabian; Müller-Rischart, Anne Kathrin; Conradt, Barbara

doi:10.18632/aging.100812

Cited by 25 publications

(20 citation statements)

References 32 publications

(56 reference statements)

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“…The mitochondrial unfolded protein response is triggered by this imbalance for restoration of mitochondrial proteostasis. These distinct pathways are coordinated in response to LRPPRC defects (Kohler et al, 2015). Although maintaining normal ATP levels by compensatory mechanisms, LSFC fibroblasts with reduced LRPPRC show impaired OXPHOS capacity, reduced membrane potential, calcium retention capacity and O 2 consumption, and increased sensitivity to Ca 2+ -induced permeability transition.…”

Section: Introductionmentioning

confidence: 99%

LRPPRC: A Multifunctional Protein Involved in Energy Metabolism and Human Disease

et al. 2019

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The pentatricopeptide repeat (PPR) family plays a major role in RNA stability, regulation, processing, splicing, translation, and editing. Leucine-rich PPR-motif-containing protein (LRPPRC), a member of the PPR family, is a known gene mutation that causes Leigh syndrome French–Canadian. Recently, growing evidence has pointed out that LRPPRC dysregulation is related to various diseases ranging from tumors to viral infections. This review presents available published data on the LRPPRC protein function and its role in tumors and other diseases. As a multi-functional protein, LRPPRC regulates a myriad of biological processes, including energy metabolism and maturation and the export of nuclear mRNA. Overexpression of LRPPRC has been observed in various human tumors and is associated with poor prognosis. Downregulation of LRPPRC inhibits growth and invasion, induces apoptosis, and overcomes drug resistance in tumor cells. In addition, LRPPRC plays a potential role in Parkinson's disease, neurofibromatosis 1, viral infections, and venous thromboembolism. Further investigating these new functions of LRPPRC should provide novel opportunities for a better understanding of its pathological role in diseases from tumors to viral infections and as a potential biomarker and molecular target for disease treatment.

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Section: Introductionmentioning

confidence: 99%

LRPPRC: A Multifunctional Protein Involved in Energy Metabolism and Human Disease

et al. 2019

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“…As a positive control, we used animals carrying a lf mutation of the gene spg-7 AFG3L2 (spg-7(ad2249)), which encodes a mitochondrial metalloprotease required for mitochondrial function [41]. The zcIs13 transgene shows very low baseline expression in wild-type animals and is widely used to monitor UPR mt in C. elegans [7,[9][10][11][12][13][14][42][43][44]. In the case of fzo-1(tm1133) animals, for example, its expression is induced more than 15-fold (S1C Fig).…”

Section: Resultsmentioning

confidence: 99%

“…To detect GFP and Tubulin, we used primary anti-GFP (1:1000, Roche 11814460001) and primary anti-α-Tubulin (1:5000, Abcam ab7291) antibodies and secondary horseradish peroxidase-conjugated goat anti-mouse antibodies (BioRad #1706516). To detect endogenous HSP-6, we used anti-HSP-6 (1:10,000) as described previously [42] and secondary horseradish peroxidase-conjugated goat anti-rabbit antibodies (BioRad #1706515). Blots were developed using ECL (Amersham) or ECL Prime (Amersham) according to manufacturer's protocol and images were quantified using the ChemiDoc XRS+ System (BioRad).…”

Section: Western Blot Analysismentioning

confidence: 99%

Autophagy compensates for defects in mitochondrial dynamics

et al. 2020

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Compromising mitochondrial fusion or fission disrupts cellular homeostasis; however, the underlying mechanism(s) are not fully understood. The loss of C. elegans fzo-1 MFN results in mitochondrial fragmentation, decreased mitochondrial membrane potential and the induction of the mitochondrial unfolded protein response (UPR mt). We performed a genome-wide RNAi screen for genes that when knocked-down suppress fzo-1 MFN (lf)-induced UPR mt. Of the 299 genes identified, 143 encode negative regulators of autophagy, many of which have previously not been implicated in this cellular quality control mechanism. We present evidence that increased autophagic flux suppresses fzo-1 MFN (lf)-induced UPR mt by increasing mitochondrial membrane potential rather than restoring mitochondrial morphology. Furthermore, we demonstrate that increased autophagic flux also suppresses UPR mt induction in response to a block in mitochondrial fission, but not in response to the loss of spg-7 AFG3L2 , which encodes a mitochondrial metalloprotease. Finally, we found that blocking mitochondrial fusion or fission leads to increased levels of certain types of triacylglycerols and that this is at least partially reverted by the induction of autophagy. We propose that the breakdown of these triacylglycerols through autophagy leads to elevated metabolic activity, thereby increasing mitochondrial membrane potential and restoring mitochondrial and cellular homeostasis.

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“…We speculate the PGC-1α/LRPPRC complex can reduce the damage of mitochondrial oxidative stress by inhibiting the ubiquitin/proteasome system. Knocking out LRPPRC in mammalian cells leads to the imbalance of the complex IV subunit of the mitochondrial and nuclear co-coding complex, which triggers the mtUPR 60 . Thus, we believe that PGC-1α/LRPPRC largely regulates mtUPR.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of PGC-1α influences the mitochondrial unfolded protein response (mtUPR) induced by MPP+ in human SH-SY5Y neuroblastoma cells

Cai

Shen

Weng

et al. 2020

Sci Rep

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Parkinson's disease (PD) is a common dyskinesia disease, the mitochondrial unfolded protein response (mtUPR) may be directly or indirectly involved in the occurrence and development of PD, although the exact mechanism is unclear. We established a dopaminergic neuronal-like cell model of PD, by overexpression of PGC-1α to detect evaluate the expression of proteases and molecular chaperones of involved in the mtUPR, as well as the expression of PGC-1α and LRPPRC, illustrated the distribution of LRPPRC. Remarkably, the mtUPR activation reached maximal at 24 h after MPP + treatment in SH-SY5Y cells, which the protein and transcription levels of the proteases and molecular chaperones reached maximal. The proteases and molecular chaperones were significantly increased when overexpressed PGC-1α, which indicated that PGC-1α overexpression activated the mtUPR, and PGC-1α had a protective effect on SH-SY5Y cells. The expression levels of PGC-1α and LRPPRC were significantly improved in the PGC-1α overexpression groups. LRPPRC was markedly reduced in the nucleus, suggesting that PGC-1α overexpression may play a protective role to the mitochondria through LRPPRC. Our finding indicates that overexpression of PGC-1α may activate mtUPR, reducing the oxidative stress injury induced by MPP + through LRPPRC signaling, thus maintain mitochondrial homeostasis. Parkinson's disease (PD) is a common neurodegenerative disease characterized by the formation of Lewy bodies and the degeneration of dopaminergic neurons in the dense parts of the substantia nigra (SN) and striatum 1. At present, the pathogenesis of PD remains unclear. Nonetheless, mitochondrial dysfunction is closely associated with protein quality control (PQC) 2 , and PQC disorder plays a very important role in the pathogenesis of PD 3. Mitochondrial protein quality control (mtPQC) is the principal mechanism that maintainscell homeostasis. Among the pathways triggered by stress, the mitochondrial unfolded protein response (mtUPR) acts to restore proteostasis specifically within the mitochondria. The mtUPR reacts to mitochondrial proteotoxic stresses, such as the accumulation of unfolded or misfolded proteins, leading to upregulated expression of mitochondrial molecular chaperones (such as the heat shock proteins (HSPs) HSPE1, HSP60 and HSPA9) and proteases (such as CLPP, Lon, YME1L1, afg3l2 and SPG7) encoded by nuclear genes 4-7. The mtUPR assists newly synthesized proteins folding correctly and it helps in the repair of misfolded or aggregated proteins, and the proteolytic removal of irreversibly damaged protein. Thus, the mtUPR is a mitochondrial-to-nuclear retrograde signal transduction pathway 8 that ensures the quality of the mitochondrial proteome. Many factors and various compounds can induce the mtUPR. Paraquat (an herbicide) and rotenone (a pesticide) are common toxins that trigger the mammalian mtUPR by inducing mitochondrial dysfunction 9-11 , both of

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The loss of LRPPRC function induces the mitochondrial unfolded protein response

Cited by 25 publications

References 32 publications

LRPPRC: A Multifunctional Protein Involved in Energy Metabolism and Human Disease

LRPPRC: A Multifunctional Protein Involved in Energy Metabolism and Human Disease

Autophagy compensates for defects in mitochondrial dynamics

Overexpression of PGC-1α influences the mitochondrial unfolded protein response (mtUPR) induced by MPP+ in human SH-SY5Y neuroblastoma cells

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