PINK1-Parkin Mitophagy Project

Bottom line: scoped, not yet started as a project. In PINK1-Parkin
mitophagy, the PINK1 kinase accumulates on damaged mitochondria and makes
phospho-ubiquitin, which activates the Parkin (PRKN) E3 ligase; ubiquitin-binding
receptors (OPTN, CALCOCO2, SQSTM1, TAX1BP1, NBR1) then link the organelle to
the autophagosome. The candidate table below lists 14 human genes, but there is
no mitophagy module and PINK1 and PRKN themselves have not been reviewed. Eight
candidates already have reviews made for Proteostasis and other projects (OPTN,
CALCOCO2, SQSTM1, TAX1BP1, NBR1, TBK1, BNIP3L, VCP). In those reviews mitophagy
is a core function of OPTN (type 2 mitophagy, GO:0061734), CALCOCO2 and
BNIP3L, and a non-core role of SQSTM1. BNIP3, FUNDC1, PHB2 and MFN2 are also
unreviewed. The worm counterpart, CAEEL_MITOPHAGY, is
much further along.

Overview

Mitophagy is the selective autophagy of damaged mitochondria. The PINK1-Parkin pathway is the best-characterized mitophagy pathway, where mitochondrial damage stabilizes PINK1 kinase, which recruits and activates the Parkin E3 ubiquitin ligase.

Model Species

Primary: Homo sapiens (human)
- Parkinson's disease relevance
- Well-characterized pathway

Core Pathway Architecture

1. Damage Sensing

• PINK1 - Kinase, stabilized on damaged mitochondria
• TOMM complex - PINK1 import/stabilization

2. Ubiquitin Ligase

• PRKN (Parkin) - E3 ubiquitin ligase
• Phospho-ubiquitin - PINK1 product, Parkin activator

3. Mitophagy Receptors

Ubiquitin-binding autophagy receptors:
- OPTN - Optineurin
- CALCOCO2 (NDP52) - Autophagy receptor
- SQSTM1 (p62) - Autophagy receptor
- TAX1BP1 - Autophagy receptor
- NBR1 - Autophagy receptor

4. Autophagy Machinery

• ULK1 complex - Initiation
• LC3/GABARAP - Autophagosome proteins
• TBK1 - Phosphorylates receptors

5. Alternative Mitophagy

PINK1/Parkin-independent:
- BNIP3/BNIP3L (NIX) - Receptor-mediated
- FUNDC1 - Hypoxia-induced
- PHB2 - Inner membrane receptor

Candidate Genes (14)

Disease Relevance

• Parkinson's disease (PINK1, PRKN mutations)
• ALS (OPTN, TBK1 mutations)
• Mitochondrial diseases

Project Status

• [ ] Stub - needs gene folder setup

Slides

• Slides (Marp source: MITOPHAGY-slides.md) — AI generated