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Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis.

ABSTRACT: Both mitochondria and lysosomes are essential for maintaining cellular homeostasis, and dysfunction of both organelles has been observed in multiple diseases. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network, which drives cellular metabolism. Lysosomes similarly undergo constant dynamic regulation by the RAB7 GTPase, which cycles from an active GTP-bound state into an inactive GDP-bound state upon GTP hydrolysis. Here we have identified the formation and regulation of mitochondria-lysosome membrane contact sites using electron microscopy, structured illumination microscopy and high spatial and temporal resolution confocal live cell imaging. Mitochondria-lysosome contacts formed dynamically in healthy untreated cells and were distinct from damaged mitochondria that were targeted into lysosomes for degradation. Contact formation was promoted by active GTP-bound lysosomal RAB7, and contact untethering was mediated by recruitment of the RAB7 GTPase-activating protein TBC1D15 to mitochondria by FIS1 to drive RAB7 GTP hydrolysis and thereby release contacts. Functionally, lysosomal contacts mark sites of mitochondrial fission, allowing regulation of mitochondrial networks by lysosomes, whereas conversely, mitochondrial contacts regulate lysosomal RAB7 hydrolysis via TBC1D15. Mitochondria-lysosome contacts thus allow bidirectional regulation of mitochondrial and lysosomal dynamics, and may explain the dysfunction observed in both organelles in various human diseases.

SUBMITTER: Wong YC

PROVIDER: S-EPMC6209448 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis.

Wong Yvette C YC Ysselstein Daniel D Krainc Dimitri D

Nature 20180124 7692

Both mitochondria and lysosomes are essential for maintaining cellular homeostasis, and dysfunction of both organelles has been observed in multiple diseases. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network, which drives cellular metabolism. Lysosomes similarly undergo constant dynamic regulation by the RAB7 GTPase, which cycles from an active GTP-bound state into an inactive GDP-bound state upon GTP hydrolysis. Here we have identifie ...[more]

PMID: 29364868

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Project description:Rationale: Ischemic heart disease remains a primary threat to human health, while its precise etiopathogenesis is still unclear. TBC domain family member 15 (TBC1D15) is a RAB7 GTPase-activating protein participating in the regulation of mitochondrial dynamics. This study was designed to explore the role of TBC1D15 in acute myocardial infarction (MI)-induced cardiac injury and the possible mechanism(s) involved. Methods: Mitochondria-lysosome interaction was evaluated using transmission electron microscopy and live cell time-lapse imaging. Mitophagy flux was measured by fluorescence and western blotting. Adult mice were transfected with adenoviral TBC1D15 through intra-myocardium injection prior to a 3-day MI procedure. Cardiac morphology and function were evaluated at the levels of whole-heart, cardiomyocytes, intracellular organelles and cell signaling transduction. Results: Our results revealed downregulated level of TBC1D15, reduced systolic function, overt infarct area and myocardial interstitial fibrosis, elevated cardiomyocyte apoptosis and mitochondrial damage 3 days after MI. Overexpression of TBC1D15 restored cardiac systolic function, alleviated infarct area and myocardial interstitial fibrosis, reduced cardiomyocyte apoptosis and mitochondrial damage although TBC1D15 itself did not exert any myocardial effect in the absence of MI. Further examination revealed that 3-day MI-induced accumulation of damaged mitochondria was associated with blockade of mitochondrial clearance because of enlarged defective lysosomes and subsequent interrupted mitophagy flux, which were attenuated by TBC1D15 overexpression. Mechanistic studies showed that 3-day MI provoked abnormal mitochondria-lysosome contacts, leading to lysosomal enlargement and subsequently disabled lysosomal clearance of damaged mitochondria. TBC1D15 loosened the abnormal mitochondria-lysosome contacts through both the Fis1 binding and the RAB7 GAPase-activating domain of TBC1D15, as TBC1D15-dependent beneficial responses were reversed by interference with either of these two domains both in vitro and in vivo. Conclusions: Our findings indicated a pivotal role of TBC1D15 in acute MI-induced cardiac anomalies through Fis1/RAB7 regulated mitochondria-lysosome contacts and subsequent lysosome-dependent mitophagy flux activation, which may provide a new target in the clinical treatment of acute MI.

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Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis.

Publications

Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis.

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