2026-10-21 — Full re-review, independent of the ProtNLM2 predictions
Folder created with just fetch-gene mouse Q8C6I2 --alias Sdhaf2__Q8C6I2. The sibling folder
genes/mouse/Sdhaf2 is keyed to the alternative product A0A494B8X4. This folder holds the
reviewed Swiss-Prot canonical product. No ProtNLM2 files or prediction-evidence folders were
opened.
Deep research
just deep-research-falcon mouse Sdhaf2__Q8C6I2 --fallback perplexity-lite failed. Falcon
returned "Failed to authenticate", and the perplexity-lite fallback returned HTTP 401 for
insufficient quota. No deep-research file was produced for this folder. The review therefore
rests on the cached primary literature (below), the UniProt record, PANTHER/PAINT data, and the
complete human SDHAF2 review. I read the same-gene falcon report in genes/mouse/Sdhaf2/ (not a
ProtNLM file) only to find mouse-specific literature, which led to PMID:38569044. I then read
that paper directly in the cache.
Evolutionary grounding
- Q8C6I2 is in PANTHER PTHR12469:SF2 ("SUCCINATE DEHYDROGENASE ASSEMBLY FACTOR 2,
MITOCHONDRIAL"; interpro/panther/PTHR12469/PTHR12469-entries.csv), the same subfamily as
human Q9NX18 and yeast Sdh5.
- PAINT IBDs at PTN000279729 (taxon 2759): GO:0005739, GO:0006099, GO:0006121 and GO:0034553.
The seeds are yeast Sdh5, human SDHAF2 and Arabidopsis AT5G51040
(interpro/panther/PTHR12469/PTHR12469-paint.tsv). PAINT did not propagate protein-FAD
linkage or a molecular function at this node. The mouse protein-FAD linkage annotation
arrives by ISO/ISS from human, not by IBA. I treat it as a sound orthology transfer within
the same subfamily, and this is recorded as inferred for mouse.
- HAMAP MF_03057 (UniRule) supplies the function, matrix location and family statements in
UniProt.
Mouse-specific experimental evidence
- PMID:18614015 (MitoCarta): Sdhaf2 detected by mass spectrometry of mitochondria from mouse
tissues (HDA, mitochondrion).
- PMID:38569044 (Zhou et al. 2024, Sci Adv): in Drp1-deficient mouse muscle and C2C12 cells,
mitochondrial Sdhaf2 is reduced while total Sdhaf2 is not, and complex II assembly is
selectively reduced (BN-PAGE). PMID:38569044 Sdhaf2 overexpression rescues succinate-dependent
RCR, fatty-acid oxidation and insulin action in myocytes. Sdhaf2 is present in the cytosolic
fraction of myotubes. The Drp1-Sdhaf2 interaction was shown by proximity ligation in mouse
C2C12 cells and with recombinant human proteins in vitro. The in vivo perturbation was Drp1,
not Sdhaf2.
- PMID:23983127 (Liu et al. 2013, JBC): PMID:23983127
The GSK-3beta/beta-catenin mechanism comes mostly from human lung cancer cells. The cache
lacks the results and figure legends.
Not established in mouse: SDHA binding, covalent flavinylation of SDHA, and chaperone activity.
These are inferred from human SDHAF2 (PMID:19628817, PMID:32887801), yeast Sdh5 and bacterial
SdhE, all in the same family.
Decisions
- Complex II assembly (GO:0034553) and protein-FAD linkage (GO:0018293): ACCEPT (core).
- Mitochondrial matrix: ACCEPT. Mitochondrion (5 rows): MODIFY to matrix, because the term is
correct but general.
- TCA cycle and succinate-to-ubiquinone electron transport: MARK_AS_OVER_ANNOTATED. Sdhaf2 is an
assembly factor, not a catalytic subunit (necessity, not participation), which matches the
human review.
- Nucleolus (ISO): MARK_AS_OVER_ANNOTATED. The human source annotation is no longer present, and
a nucleolar pool conflicts with the matrix function and with the mouse fractionation data.
- Cytosol (ISO): KEEP_AS_NON_CORE. A pre-import pool is confirmed in mouse myotubes.
- EMT, Wnt and protein dephosphorylation (IMP/ISO/IEA): KEEP_AS_NON_CORE, deferring to the MGI
curators. These effects are indirect and context-dependent.
- ND molecular_function: MODIFY to GO:0044183 protein folding chaperone. This is inferred
through the SF2 subfamily from the human structure; it is not a mouse experiment.
- No NEW annotations. The Drp1 interaction was not added as an MF; "protein binding" is
uninformative.