Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis

Fernández-Mosquera, Lorena; Diogo, Cátia V.; Yambire, King Faisal; Santos, Gabriela L.; Luna-Sánchez, Marta; Bénit, Paule; Rustin, Pierre; López, Luís C.; Milošević, Ira; Raimundo, Nuno

doi:10.1038/srep45076

Cited by 78 publications

(76 citation statements)

References 30 publications

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“…The existence of communication mechanisms linking mitochondria and lysosomes may be responsible for the potential alterations in Opa1‐deficient cells. Thus, mitochondrial dysfunction has been reported to promote enhanced lysosomal biogenesis in some conditions, and reduced lysosomal function (Baixauli et al , ; Demers‐Lamarche et al , ; Fernandez‐Mosquera et al , ). Alternatively, Opa1 deficiency may regulate mTOR, which has been reported to regulate mitochondrial activity through translational control (Morita et al , ).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency

et al. 2018

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Opa1 participates in inner mitochondrial membrane fusion and cristae morphogenesis. Here, we show that muscle-specific Opa1 ablation causes reduced muscle fiber size, dysfunctional mitochondria, enhanced Fgf21, and muscle inflammation characterized by NF-κB activation, and enhanced expression of pro-inflammatory genes. Chronic sodium salicylate treatment ameliorated muscle alterations and reduced the muscle expression of Fgf21. Muscle inflammation was an early event during the progression of the disease and occurred before macrophage infiltration, indicating that it is a primary response to Opa1 deficiency. Moreover, Opa1 repression in muscle cells also resulted in NF-κB activation and inflammation in the absence of necrosis and/or apoptosis, thereby revealing that the activation is a cell-autonomous process and independent of cell death. The effects of Opa1 deficiency on the expression NF-κB target genes and inflammation were absent upon mitochondrial DNA depletion. Under Opa1 deficiency, blockage or repression of TLR9 prevented NF-κB activation and inflammation. Taken together, our results reveal that Opa1 deficiency in muscle causes initial mitochondrial alterations that lead to TLR9 activation, and inflammation, which contributes to enhanced Fgf21 expression and to growth impairment.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency

et al. 2018

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“…We and others have recently unveiled several signaling pathways by which deficient mitochondria result in lysosomal impairment, or vice-versa (Demers-Lamarche et al, 2016;Fernandez-Mosquera et al, 2017;Fernandez-Mosquera et al, 2019;Osellame et al, 2013;Yambire et al, 2019). This mutually destructive relationship between mitochondria and lysosomes is particularly detrimental in neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Impaired lysosomal acidification triggers iron deficiency, necrotic cell death and inflammationin vivo

Yambire

Rostosky

Watanabe

et al. 2019

Preprint

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RESULTS v-ATPase inhibition triggers hypoxia-inducible factor-mediated responseWith the goal of identifying signaling events caused by impaired organelle acidification, we analyzed several transcriptome datasets of cells treated with the v-ATPase inhibitor bafilomycin. These datasets include bafilomycin treatment of HeLa cells (GSE16870) (Straud et al., 2010), colon carcinoma cells (GSE47836) (Durrbaum et al., 2014) and retinal pigment epithelial cells (GSE60570) (Santaguida et al., 2015). We performed multi-dimensional transcriptome analysis in these datasets, aiming at the identification of signaling pathways, networks and transcription factors (Murdoch et al., 2016;Raimundo et al., 2012;Raimundo et al., 2009;Schroeder et al., 2013;Tyynismaa et al., 2010;West et al., 2015;Yambire et al., 2019). We reasoned that those transcription factors (TF) showing similar behavior in the three datasets of bafilomycin-treated cells would be the main regulators of the response to loss of acidification, independently of the cell type. Therefore, we crossed the TF list associated with each dataset, to determine which of those were involved in all three datasets, and found eight common TF, of which seven were predicted as active and one as repressed ( Figure 1A). These TF are associated with autophagy (NUPR1), cholesterol homeostasis (SREBF1, SREBF2), hypoxia response (HIF-1α and EPAS1, which is also known as HIF-2α) and diverse stress responses (p53, myc, FoxO3a), and form a highly interconnected network ( Figure 1B). To determine which biological processes were associated with these TF, and identify which of them were most upstream, we performed a pathway analysis using Metascape, and found that the most affected processes dealt with cellular response to hypoxia ( Figure 1C).The major coordinator of the cellular reponse to hypoxia is the transcription factor hypoxiainducible factor-1α (Majmundar et al., 2010), which is included in the list of TFs responding to bafilomycin. Furthermore, HIF-2α (EPAS1), whose activation mechanism is similar to HIF-1α, is also part of the TF list. The HIF transcription factors function as heterodimers of a regulated α-subunit and the constitutive β subunit (Majmundar et al., 2010). The α subunits are regulated post-translationally by the prolyl hydroxylases. These enzymes are dioxygenases of the α-ketoglutarate-dependent superfamily, and hydroxylate HIF-1α and HIF-2α in the presence of O2, Fe 2+ and α-ketoglutarate (Majmundar et al., 2010). Hydroxylated HIF-1α and HIF-2α are then recognized by the ubiquitin ligase VHL and targeted to the proteasome for degradation. Notably, the protein levels of HIF-1α were increased in bafilomycin (Baf)-treated fibroblasts ( Figure 1D). A similar result was obtained in cells treated with a different inhibitor of the lysosomal v-ATPase, saliphenylhalamide (henceforth, saliphe [or Sal in figures]) ( Figure 1D). Accumulation of HIF-1α can be caused by decreased function of the prolyl hydroxylases or decreased levels of O2 or VHL (Raimundo et al., 2011). Because the...

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“…Supporting this, autophagy enhancing drugs such as rapamycin has neuroprotective effects against the mitochondrial complex I inhibitor rotenone in cellular models of PD (21). Interestingly, mitochondrial dysfunction induced by rotenone treatment alters the expression of lysosomal genes, which perhaps is explained by the fact that mitophagy induction through nuclear translocation of transcription factors regulates mitochondrial and lysosomal biogenesis (22,23). Recent studies have documented mitochondria-lysosome membrane contact sites, which enable bidirectional regulation of mitochondrial and lysosomal dynamics, and have demonstrated how mitochondrial impairment supresses autophagic flux, overall suggesting a complex mutual relationship between these two cellular compartments (24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 95%

Lysosomal perturbations in dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Okarmus

Bogetofte

Schmidt

et al. 2019

Preprint

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Mutations in the PARK2 gene encoding parkin, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinson's disease (PD). While parkin has been implicated in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration in both sporadic and familial PD upon parkin loss-of-function mutations remains unknown. Cultures of isogenic induced pluripotent stem cell (iPSC) lines with and without PARK2 knockout (KO) enable mechanistic studies of the effect of parkin deficiency in human dopaminergic neurons. In the present study, we used such cells to investigate the impact of PARK2 KO on the lysosomal compartment combining different approaches, such as mass spectrometry-based proteomics, electron microscopy (TEM) analysis and functional assays. We discovered a clear link between parkin deficiency and lysosomal alterations. PARK2 KO neurons exhibited a perturbed lysosomal morphology, displaying significantly enlarged and electron-lucent lysosomes as well as an increased total lysosomal content, which was exacerbated by mitochondrial stress. In addition, we found perturbed autophagic flux and decreased lysosomal enzyme activity suggesting an impairment of the autophagylysosomal pathway in parkin-deficient cells. Interestingly, activity of the GBA-encoded enzyme, b-glucocerebrosidase, was significantly increased suggesting the existence of a compensatory mechanism. In conclusion, our data provide a unique characterization of the morphology, content, and function of lysosomes in PARK2 KO neurons, thus revealing a new important connection between mitochondrial dysfunction and lysosomal dysregulation in PD pathogenesis.

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Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis

Cited by 78 publications

References 30 publications

Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency

Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency

Impaired lysosomal acidification triggers iron deficiency, necrotic cell death and inflammationin vivo

Lysosomal perturbations in dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

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