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 diseases1–4. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network, which drives cellular metabolism 5. Lysosomes similarly undergo constant dynamic regulation by the RAB7 GTPase 1, 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 6,7. 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.

Super‐Resolution Tracking of Mitochondrial Dynamics with An Iridium(III) Luminophore

“…The interactions of mitochondria and lysosomes, including their fusion involved in mitophagy, are essential for repairing damaged mitochondria. Recently, a direct contact between mitochondria and lysosome was demonstrated in normal living cells . To investigate the crosstalk of mitochondria and lysosomes, we used our dye together with commercial LysoTracker Green to label lysosomes in mammalian cells.…”

“…During that process, several receptors (i.e., p62, NDP52, OPTN, NBR1, and TAX1BP1) play an important role . Therefore, it is reasonable to check whether these mitophagy proteins are involved in MLC events other than the recently reported RAB7GTP hydrolysis . To investigate the correlation between MLC and fusion, we performed the SIM experiment in Penta knockout (KO) HeLa cells which are deficient of mitophagy.…”

Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery

“…Secondly, emerging evidence shows that Fis1 is also involved in Drp1‐ and/or Dyn2‐independent mitochondrial fission, for instance, depletion of Drp1 and/or Dyn2 only partially reduced hFis1‐induced mitochondrial fragmentation as described in the work presented here as well as in a previous study (Yoon et al , ). In this regard, a recent report has elucidated a new and intriguing role of Fis1 in mitochondrial fission via mitochondria–lysosome contacts, where TBC1D15, a Rab7 GTPase‐activating protein, is recruited to mitochondria by hFis1 to drive lysosomal Rab7 GTP hydrolysis, thereby regulating both lysosomal and mitochondrial dynamics (Wong et al , ). This finding is corroborated by a study showing that expression of Fis1 or co‐expression of Fis1 and TBC1D15 induces mitochondrial fragmentation in Drp1‐knockout mouse embryonic fibroblasts (MEFs), suggesting that Fis1 and TBC1D15 function independently of Drp1 (Onoue et al , ).…”

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

“…In addition, dynamic interorganelle contact sites were recently identified between mitochondria and lysosomes, demonstrating that these two organelles physically interact with one another independently of mitophagy or lysosomal engulfment of mitochondria to mediate their functional crosstalk. Mitochondria‐lysosome contact sites allowed for bidirectional regulation of network dynamics of both organelles whereby lysosomal contacts marked sites of mitochondrial fission allowing regulation of mitochondrial dynamics by lysosomes. Conversely, mitochondrial contacts regulated the lysosomal RAB7 guanosine triphosphate state, which is a master regulator of lysosomal dynamics .…”

“…Mitochondria‐lysosome contact sites allowed for bidirectional regulation of network dynamics of both organelles whereby lysosomal contacts marked sites of mitochondrial fission allowing regulation of mitochondrial dynamics by lysosomes. Conversely, mitochondrial contacts regulated the lysosomal RAB7 guanosine triphosphate state, which is a master regulator of lysosomal dynamics . Thus, mitochondria–lysosome contact sites may contribute to the dysfunction observed in both organelles in PD, and misregulation of these contacts may exacerbate defective mitochondrial dynamics critical for nigral dopaminergic neuron survival …”