RRC ID 65225
Author Vrijsen S, Besora-Casals L, van Veen S, Zielich J, Van den Haute C, Hamouda NN, Fischer C, Ghesquière B, Tournev I, Agostinis P, Baekelandt V, Eggermont J, Lambie E, Martin S, Vangheluwe P.
Title ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress.
Journal Proc Natl Acad Sci U S A
Abstract Recessive loss-of-function mutations in ATP13A2 (PARK9) are associated with a spectrum of neurodegenerative disorders, including Parkinson's disease (PD). We recently revealed that the late endo-lysosomal transporter ATP13A2 pumps polyamines like spermine into the cytosol, whereas ATP13A2 dysfunction causes lysosomal polyamine accumulation and rupture. Here, we investigate how ATP13A2 provides protection against mitochondrial toxins such as rotenone, an environmental PD risk factor. Rotenone promoted mitochondrial-generated superoxide (MitoROS), which was exacerbated by ATP13A2 deficiency in SH-SY5Y cells and patient-derived fibroblasts, disturbing mitochondrial functionality and inducing toxicity and cell death. Moreover, ATP13A2 knockdown induced an ATF4-CHOP-dependent stress response following rotenone exposure. MitoROS and ATF4-CHOP were blocked by MitoTEMPO, a mitochondrial antioxidant, suggesting that the impact of ATP13A2 on MitoROS may relate to the antioxidant properties of spermine. Pharmacological inhibition of intracellular polyamine synthesis with α-difluoromethylornithine (DFMO) also increased MitoROS and ATF4 when ATP13A2 was deficient. The polyamine transport activity of ATP13A2 was required for lowering rotenone/DFMO-induced MitoROS, whereas exogenous spermine quenched rotenone-induced MitoROS via ATP13A2. Interestingly, fluorescently labeled spermine uptake in the mitochondria dropped as a consequence of ATP13A2 transport deficiency. Our cellular observations were recapitulated in vivo, in a Caenorhabditis elegans strain deficient in the ATP13A2 ortholog catp-6 These animals exhibited a basal elevated MitoROS level, mitochondrial dysfunction, and enhanced stress response regulated by atfs-1, the C. elegans ortholog of ATF4, causing hypersensitivity to rotenone, which was reversible with MitoTEMPO. Together, our study reveals a conserved cell protective pathway that counters mitochondrial oxidative stress via ATP13A2-mediated lysosomal spermine export.
Volume 117(49)
Pages 31198-31207
Published 2020-12-8
DOI 10.1073/pnas.1922342117
PII 1922342117
PMID 33229544
PMC PMC7733819
MeSH Activating Transcription Factor 4 / genetics* Adenosine Triphosphatases / genetics* Animals Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics* Eflornithine / pharmacology Fibroblasts / drug effects Lysosomes / genetics Lysosomes / metabolism Mitochondria / drug effects Mitochondria / genetics* Mitochondria / pathology Mutation / genetics Oxidative Stress / drug effects Parkinson Disease / genetics Parkinson Disease / pathology Polyamines / metabolism Proton-Translocating ATPases / genetics* Rotenone / pharmacology Spermine / metabolism Transcription Factor CHOP / genetics Transcription Factors / genetics*
C.elegans tm4481