LRRK2 regulates endoplasmic reticulum–mitochondrial tethering through the PERK‐mediated ubiquitination pathway

• Published in: The EMBO journal Vol. 39; no. 2; pp. e100875 - n/a
• Main Authors: Toyofuku, Toshihiko, Okamoto, Yuki, Ishikawa, Takako, Sasawatari, Shigemi, Kumanogoh, Atsushi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-01-2020; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Activation; Animals; Bioenergetics; Calcium (mitochondrial); Calcium ions; Cell fate; Cells, Cultured; Degradation; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; EMBO07; EMBO20; EMBO21; Embryo fibroblasts; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; Embryos; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Evolution; Fibroblasts; Fibroblasts - cytology; Fibroblasts - metabolism; Kinases; Leucine; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; LRRK2; LRRK2 protein; Mice; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Movement disorders; Mutation; Neurodegenerative diseases; Parkin protein; Parkinson's disease; Pathogenesis; PERK; Phosphorylation; Proteasomes; Protein interaction; Proteins; Tethering; Ubiquitin; Ubiquitin - metabolism; ubiquitin ligase; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; ubiquitin ligase; PERK; LRRK2; mitochondria; endoplasmic reticulum
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2018100875

Mutations in the leucine‐rich repeat kinase 2 (
LRRK2
) gene are the most common cause of familial Parkinson's disease (PD). Impaired mitochondrial function is suspected to play a major role in PD. Nonetheless, the underlying mechanism by which impaired LRRK2 activity contributes to PD pathology remains unclear. Here, we identified the role of LRRK2 in endoplasmic reticulum (ER)–mitochondrial tethering, which is essential for mitochondrial bioenergetics. LRRK2 regulated the activities of E3 ubiquitin ligases MARCH5, MULAN, and Parkin via kinase‐dependent protein–protein interactions. Kinase‐active LRRK2(G2019S) dissociated from these ligases, leading to their PERK‐mediated phosphorylation and activation, thereby increasing ubiquitin‐mediated degradation of ER–mitochondrial tethering proteins. By contrast, kinase‐dead LRRK2(D1994A)‐bound ligases blocked PERK‐mediated phosphorylation and activation of E3 ligases, thereby increasing the levels of ER–mitochondrial tethering proteins. Thus, the role of LRRK2 in the ER–mitochondrial interaction represents an important control point for cell fate and pathogenesis in PD.
Synopsis
The contribution of mitochondrial dysfunction to Parkinson's disease remains unclear. Here, the mitochondrial ubiquitination system is identified as a new regulatory target of leucine‐rich repeat kinase 2 (LRRK2), revealing a functional link between vulnerability to endoplasmic reticulum (ER) stress and dynamics of the ER‐mitochondria interface.
LRRK2 mutation decreases mitochondrial biogenesis, respiration and proteasomal degradation in mouse embryonic fibroblasts.
LRRK2 mutation alters ER‐mitochondrial Ca
2+
transfer and sensitivity to ER stress.
PERK phosphorylates mitochondrial E3 ubiquitin ligases and decreases the formation of mitochondria‐associated ER membranes under stress.
Kinase‐dead LRRK2 binds E3 ubiquitin ligases and abrogates their PERK‐mediated activation.
Graphical Abstract
LRKK2 mutation counteracts PERK‐mediated activation of E3 ubiquitin ligases and controls mitochondria‐associated ER membrane formation.