Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient <i>Pex19</i> mutants

Bülow, Margret H.; Wingen, Christian; Senyilmaz, Deniz; Gosejacob, Dominic; Sociale, Mariangela; Bauer, Reinhard; Schulze, Heike; Sandhoff, Konrad; Teleman, Aurelio A.; Hoch, Michael; Sellin, Julia

doi:10.1091/mbc.e17-08-0535

Cited by 45 publications

(56 citation statements)

References 47 publications

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“…We found that the loss of peroxisomes induced the fragmentation of mitochondria, whereas some previous studies showed that the loss of peroxisomes promoted the enlargement of mitochondria (Bülow et al, 2018; Rahim et al, 2016). This difference may be attributable to the long-term ablation of peroxins in these previous studies, which likely resulted in secondary effects due to the accumulation of ROS and subsequent cellular damage.…”

Section: Discussioncontrasting

confidence: 75%

“…We next addressed the mechanism by which the diffusion of cytochrome c is increased in peroxisome-deficient MEFs. Although previous studies have shown that long-term deletion of Pex genes results in ROS accumulation (Bülow et al 2018, Rahim et al 2016), the cytosolic ROS level of our Pex3-deficient MEFs as measured with CellROX did not appear to differ from that of control MEFs (Fig. 6,A and B).…”

Section: Resultscontrasting

confidence: 54%

“…Deletion of Pex5 was also shown to increase the number of mitochondria as well as the level of glycolytic activity, possibly as a compensatory response to the impairment of OXPHOS (Peeters et al, 2015). Deletion of Pex13 in mouse brain or of Pex19 in fly larvae resulted in similar dysfunction of OXPHOS, elevated ROS levels, and an increased abundance of mitochondria (Bülow et al, 2018; Rahim et al, 2016). Furthermore, human patients harboring PEX16 mutations manifest myopathy accompanied by mitochondrial abnormalities (Salpietro et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Peroxisomes control mitochondrial dynamics and the mitochondrion-dependent pathway of apoptosis

Tanaka

Okazaki

Yokota

et al. 2018

Preprint

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Summary StatementsWe unveil a previously unrecognized role of peroxisomes in the regulation of mitochondrial fission-fusion dynamics, mitochondrion-dependent caspase activation, and cellular apoptosis.AbstractPeroxisomes cooperate with mitochondria in the performance of cellular metabolic functions such as fatty acid oxidation and maintenance of redox homeostasis. Whether peroxisomes also regulate mitochondrial fission-fusion dynamics or mitochondrion-dependent apoptosis has remained unclear, however. We now show that genetic ablation of the peroxins Pex3 or Pex5, which are essential for peroxisome biogenesis, resulted in mitochondrial fragmentation in mouse embryonic fibroblasts (MEFs) in a manner dependent on dynamin-related protein 1 (Drp1). Conversely, treatment with 4-phenylbutyric acid, an inducer of peroxisome proliferation, resulted in mitochondrial elongation in wild-type MEFs, but not in Pex3-deficient MEFs. We further found that peroxisome deficiency increased the levels of cytosolic cytochrome c and caspase activity under basal conditions without inducing apoptosis. It also greatly enhanced etoposide-induced caspase activation and apoptosis, indicative of an enhanced cellular sensitivity to death signals. Together, our data unveil a previously unrecognized role of peroxisomes in the regulation of mitochondrial dynamics and mitochondrion-dependent apoptosis. Given that mutations of peroxin genes are responsible for lethal disorders such as Zellweger syndrome, effects of such mutations on mitochondrion-dependent apoptosis may contribute to disease pathogenesis.

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Section: Discussioncontrasting

confidence: 75%

Section: Resultscontrasting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

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Peroxisomes control mitochondrial dynamics and the mitochondrion-dependent pathway of apoptosis

Tanaka

Okazaki

Yokota

et al. 2018

Preprint

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“…A recent study employing Drosophila melanogaster and human fibroblasts has linked mitochondrial dysfunctionality in PEX19 deletion cells with a detrimental cycle of transcriptionally activated constant fatty acid synthesis and mitochondrial β‐oxidation . Although this study suggests an interesting link between peroxisomes/lipid droplets and mitochondria, a similar conclusion cannot be drawn for yeast cells because they do not possess a homologous transcriptional regulation mechanism, which can be responsible for the vicious cycle, and yeast mitochondria do not perform β‐oxidation.…”

Section: Discussionmentioning

confidence: 59%

Pex19 is involved in importing dually targeted tail‐anchored proteins to both mitochondria and peroxisomes

Cichocki

Krumpe

Vitali

et al. 2018

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Tail-anchored (TA) proteins are embedded into their corresponding membrane via a single transmembrane segment at their C-terminus whereas the majority of the protein is facing the cytosol. So far, cellular factors that mediate the integration of such proteins into the mitochondrial outer membrane were not found. Using budding yeast as a model system, we identified the cytosolic Hsp70 chaperone Ssa1 and the peroxisome import factor Pex19 as import mediators for a subset of mitochondrial TA proteins. Accordingly, deletion of PEX19 results in: (1) growth defect under respiration conditions, (2) alteration in mitochondrial morphology, (3) reduced steady-state levels of the mitochondrial TA proteins Fis1 and Gem1, and (4) hampered in organello import of the TA proteins Fis1 and Gem1. Furthermore, recombinant Pex19 can bind directly the TA proteins Fis1 and Gem1. Collectively, this work identified the first factors that are involved in the biogenesis of mitochondrial TA proteins and uncovered an unexpected function of Pex19.

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“…On the one hand, they generate H 2 O 2 as a consequence of fatty acid peroxidation; on the other hand, they contain a set of antioxidant enzymes and function therefore as reactive oxygen species (ROS) scavenging organelles [80]. Interestingly, loss of Pex19 in D. melanogaster causes ROS accumulation and mitochondrial damage, and a mouse model of Zellweger syndrome displays a similar phenotype [81,82]. Elevated endogenous ROS are known to induce genome instability [83,84].…”

Section: Discussionmentioning

confidence: 99%

A genome-wide screen identifies genes that suppress the accumulation of spontaneous mutations in young and aged yeast cells

Novarina

Janssens

Bokern

et al. 2018

Preprint

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To ensure proper transmission of genetic information, cells need to preserve and faithfully replicate their genome, and failure to do so leads to genome instability, a hallmark of both cancer and aging. Defects in genes involved in guarding genome stability cause several human progeroid syndromes, and an age‐dependent accumulation of mutations has been observed in different organisms, from yeast to mammals. However, it is unclear whether the spontaneous mutation rate changes during aging and whether specific pathways are important for genome maintenance in old cells. We developed a high‐throughput replica‐pinning approach to screen for genes important to suppress the accumulation of spontaneous mutations during yeast replicative aging. We found 13 known mutation suppression genes, and 31 genes that had no previous link to spontaneous mutagenesis, and all acted independently of age. Importantly, we identified PEX19, encoding an evolutionarily conserved peroxisome biogenesis factor, as an age‐specific mutation suppression gene. While wild‐type and pex19Δ young cells have similar spontaneous mutation rates, aged cells lacking PEX19 display an elevated mutation rate. This finding suggests that functional peroxisomes may be important to preserve genome integrity specifically in old cells.

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Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants

Cited by 45 publications

References 47 publications

Peroxisomes control mitochondrial dynamics and the mitochondrion-dependent pathway of apoptosis

Peroxisomes control mitochondrial dynamics and the mitochondrion-dependent pathway of apoptosis

Pex19 is involved in importing dually targeted tail‐anchored proteins to both mitochondria and peroxisomes

A genome-wide screen identifies genes that suppress the accumulation of spontaneous mutations in young and aged yeast cells

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