Mitochondria-lysosome contact site dynamics and misregulation in neurodegenerative diseases

Abstract

Neurons rely heavily on properly regulated mitochondrial and lysosomal homeostasis, with multiple neurodegenerative diseases linked to dysfunction in these two organelles. Interestingly, mitochondria-lysosome membrane contact sites have been identified as a key pathway mediating their crosstalk in neurons. Recent studies have further elucidated the regulation of mitochondria-lysosome contact dynamics via distinct tethering/untethering protein machinery. Moreover, this pathway has been shown to have additional functions in regulating organelle network dynamics and metabolite transfer between lysosomes and mitochondria. In this review, we highlight recent advances in the field of mitochondria-lysosome contact sites and their misregulation across multiple neurodegenerative disorders, which further underscore a potential role for this pathway in neuronal homeostasis and disease.

Keywords: Charcot-Marie-Tooth disease; Parkinson’s disease; inter-organelle contact sites; lysosomal storage disorders; lysosomes; mitochondria.

Figure 1.. Mitochondria-lysosome contact sites in neurons.

Mitochondria-lysosome contact sites are inter-organelle contacts which form between mitochondria and lysosomes, allowing for these organelles’ bidirectional crosstalk. Mitochondria-lysosome contact sites have been shown to form in the soma, axons and dendrites of neurons including human iPSC-derived neurons [7, 8].

Figure 2.. Regulation of mitochondria-lysosome contact site dynamics.

(A) Regulation of contact sites: Mitochondria and lysosomes undergo contact formation and tethering regulated by Rab7 on the lysosomal membrane. Active GTP-bound Rab7 may tether the lysosome to the mitochondria via various Rab7 effector proteins or protein complexes (gray). Subsequently, TBC1D15 (Rab7 GAP) which is recruited to the mitochondria by the outer mitochondrial membrane protein Fis1 drives Rab7 GTP hydrolysis from an active Rab7 GTP-bound state into an inactive Rab7 GDP-bound state at mitochondria-lysosome contacts. This transition from a GTP-bound state to a GDP-bound state leads to GDP-bound Rab7 leaving the lysosomal membrane, resulting in the subsequent untethering of mitochondria-lysosome contacts. (B) Modulation of organelle dynamics: Mitochondria-lysosome contact sites can simultaneously bidirectionally regulate both mitochondrial and lysosomal network dynamics, including mitochondrial fission events, inter-mitochondrial contact untethering and lysosomal tethering.

Figure 3.. Metabolite transfer at mitochondria-lysosome contact sites.

Mitochondria-lysosome contact sites can mediate the exchange of metabolites, such as calcium, cholesterol and iron. The transport of calcium from lysosomes to mitochondria occurs via the lysosomal membrane channel TRPML1 which promotes efflux of lysosomal calcium into the mitochondrial matrix via the outer and inner mitochondrial membrane channels VDAC1 and MCU at mitochondria-lysosome contacts. Cholesterol and iron have also been shown to be transferred from lysosomes to mitochondria at contact sites.