Mitochondrial Import Pathways Project

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:

1. MIM/MTCH pathway — α-helical outer membrane protein insertion (via Tom70 → MIM complex)
2. TOM-TIM23-PAM pathway — presequence-bearing proteins imported into the matrix
3. TOM-TIM23-SORT pathway — lateral insertion of proteins into the inner membrane via TIM23
4. TOM-SAM pathway — β-barrel outer membrane protein insertion
5. TOM-TIM22 pathway — inner membrane metabolite carrier import (carrier pathway)
6. TOM-MIA pathway — IMS protein import via the disulfide relay system (CX₃C/CX₉C motifs)
7. 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