Mitochondrial Import Pathways Project
Bottom line: almost all mitochondrial proteins are made in the cytosol and
reach their compartment by one of six routes (TOM-TIM23-PAM to the
matrix, TIM23-SORT and TIM22 to the inner membrane, SAM and MIM/MTCH to the
outer membrane, the MIA disulfide relay to the intermembrane space), but GO
grouped them inconsistently. This project follows GO issue #31711, which
proposed one GO process term per route, and reviewed the GO annotations of the
human machinery that runs them. All 23 priority genes (TOM, TIM23, PAM, TIM22,
SAM, MIA, MTCH2 and the MPP processing peptidase) now have reviews in the repo
(670 annotations: 319 accepted, 88 kept as non-core, 167 marked over-annotated,
40 modified, 50 removed, 6 NEW); the checklist below predates most of them.
GO has since added the proposed terms: the parent
GO:7770058 mitochondrial protein import pathway, GO:7770059 (α-helical
outer-membrane insertion), GO:7770060 (TIM23-SORT), GO:7770061 (TIM22) and
GO:7770063 (β-barrel insertion), and reworded GO:0030150 and GO:0160203
to name their routes. Among the 23 priority genes only MTCH2 carries one of the
new terms in its review; outside that set, human MTCH1 has an accepted IMP
annotation to GO:7770059 and yeast MIM1 is reviewed onto it. The grouping terms proposed for obsoletion, such as GO:0070585, are
still live.
Overview
Reorganization of GO terms for mitochondrial protein import pathways, driven by GO-CAM modelling work.
Based on: https://github.com/geneontology/go-ontology/issues/31711
Background
Mitochondrial protein import involves multiple distinct pathways for different classes of precursor proteins:
- MIM/MTCH pathway — α-helical outer membrane protein insertion (via Tom70 → MIM complex)
- TOM-TIM23-PAM pathway — presequence-bearing proteins imported into the matrix
- TOM-TIM23-SORT pathway — lateral insertion of proteins into the inner membrane via TIM23
- TOM-SAM pathway — β-barrel outer membrane protein insertion
- TOM-TIM22 pathway — inner membrane metabolite carrier import (carrier pathway)
- TOM-MIA pathway — IMS protein import via the disulfide relay system (CX₃C/CX₉C motifs)
- OXA pathway — inner membrane insertion of mitochondrial-encoded proteins (not import per se)
Proposed GO Term Changes (from issue #31711)
New terms proposed
- Mitochondrial protein import pathway (parent term)
- Mitochondrial outer membrane alpha helical protein insertion (MIM/MTCH pathway)
- TOM-TIM23-SORT protein import and lateral insertion into inner membrane
- Mitochondrial beta barrel outer membrane protein insertion (TOM-SAM pathway)
- TOM-TIM22 inner membrane protein import (carrier pathway)
Modifications proposed
- Rename GO:0030150 → clarify as "protein import into mitochondrial matrix" via TOM-TIM23-PAM
- Rename GO:0160203 → "protein import into intermembrane space via disulfide relay system"
Terms proposed for obsoletion
- GO:0070585, GO:0072656, GO:1903637 and others — unnecessary groupings that can be annotated to more specific pathways
Genes to Review
The project should review key components of each import pathway. Priority genes TBD based on which organisms/complexes are being modelled.
Key complexes and representative subunits
- TOM complex: TOMM40, TOMM20, TOMM22, TOMM70, TOMM5, TOMM6, TOMM7
- TIM23 complex: TIMM23, TIMM17A/B, TIMM50, TIMM21
- PAM complex: HSPA9 (mortalin/mtHsp70), TIMM44, GRPEL1/2, PAM16/TIMM16, PAM18/TIMM14
- TIM22 complex: TIMM22, TIMM29, TIMM10, AGK
- SAM/TOB complex: SAMM50, metaxin-1/2/3
- MIA/CHCHD4 pathway: CHCHD4 (Mia40), ALR/GFER (Erv1)
- MIM complex: MIM1, MIM2 (yeast); MTCH2 (metazoan equivalent)
- Processing: PMPCB, PMPCA (MPP), XPNPEP3 (Icp55), MIP/MIPEP (Oct1)
- Folding: HSPD1 (Hsp60), HSPE1 (Hsp10)
Priority Genes (fetched)
Tier 1 — Core channel/pathway subunits
| Gene | Complex/Pathway | Annotations |
|---|---|---|
| TOMM40 | TOM complex central channel | 30 |
| TIMM23 | TIM23 complex channel | 29 |
| TIMM22 | TIM22 complex channel | 27 |
| SAMM50 | SAM complex channel | 31 |
| CHCHD4 | MIA40/disulfide relay | 31 |
| GFER | Erv1/ALR, disulfide relay partner | 26 |
| MTCH2 | Metazoan MIM equivalent | 22 |
Tier 2 — Receptors, regulators, and accessory subunits
| Gene | Complex/Pathway | Annotations |
|---|---|---|
| TOMM20 | TOM receptor (presequence) | pre-existing |
| TOMM22 | TOM receptor (cis-binding) | 27 |
| TOMM70 | TOM receptor (carrier proteins) | 60 |
| TOMM5 | Small TOM subunit | 11 |
| TOMM6 | Small TOM subunit | 10 |
| TOMM7 | Small TOM subunit (quality control) | 20 |
| TIMM50 | TIM23 receptor | 32 |
| TIMM44 | PAM complex (tethers mtHsp70) | 24 |
| TIMM17A | TIM23 core channel | 17 |
| TIMM21 | TIM23-SORT pathway | 23 |
| PAM16 | PAM complex (J-protein regulator) | 27 |
| MTX1 | Metaxin-1, SAM complex partner | 16 |
| MTX2 | Metaxin-2, SAM complex partner | 20 |
| HSPA9 | Mortalin/mtHsp70 (PAM motor) | pre-existing |
Tier 3 — Processing enzymes
| Gene | Function | Annotations |
|---|---|---|
| PMPCA | MPP alpha subunit | 24 |
| PMPCB | MPP beta subunit (catalytic) | 21 |
Status
- [x] Read and understand issue #31711
- [x] Identify priority genes for review
- [x] Fetch gene data for all priority genes
- [x] Deep research on pathway components and nomenclature
- [ ] Begin gene reviews
- [x] TOMM40 — TOM complex central channel (30 annotations reviewed)
- [x] CHCHD4 — MIA40/disulfide relay (31 annotations reviewed)
- [x] MTCH2 — metazoan MIM insertase (22 annotations reviewed)
- [ ] Remaining genes (TIMM23, TIMM22, SAMM50, GFER, TOMM22, TOMM70, etc.)
- [ ] Propose GO term hierarchy
Slides
- Slides (Marp source: MITOCHONDRIAL_IMPORT_PATHWAYS-slides.md) — AI generated