| Pathway/Transcription Factor | Role in isp-1 Longevity | Key Evidence | Key Reference |
|---|---|---|---|
| HIF-1 | Required for lifespan extension | isp-1(qm150) elevates ROS and increases HIF-1 target gene expression; loss of hif-1 or aha-1 shortens the extended lifespan of isp-1 mutants, indicating HIF-1 is a key mediator of mitochondrial retrograde longevity signaling. (pqac-00000016, pqac-00000022, pqac-00000026) | Lee et al., 2010 (pqac-00000016, pqac-00000022, pqac-00000026) |
| DAF-16/FOXO | Required for full lifespan extension | DAF-16 target genes are enriched among transcripts upregulated in isp-1 mutants; DAF-16 shows increased nuclear localization, and daf-16 loss markedly suppresses isp-1 longevity. ROS appears to be an upstream activator, with IMB-2, CST-1/2, BAR-1, and MATH-33 supporting DAF-16-dependent longevity. (pqac-00000021, pqac-00000023, pqac-00000024, pqac-00000025) | Senchuk et al., 2018 (pqac-00000021, pqac-00000023, pqac-00000024, pqac-00000025) |
| SKN-1/Nrf2 | Required for lifespan extension | SKN-1 target genes are activated in isp-1 mutants, and SKN-1 is required for the increased longevity of mitochondrial mutants including isp-1, supporting a ROS-responsive oxidative stress program downstream of ETC dysfunction. (pqac-00000020) | Senchuk et al., 2018 (pqac-00000020) |
| ATFS-1/mitoUPR | Dispensable for adult lifespan extension; required for development in isp-1 background | ATFS-1 is necessary for induction of mitoUPR reporters and target genes in isp-1 mutants, but adult-only atfs-1 knockdown does not reduce isp-1 lifespan. In contrast, loss of ATFS-1 during development causes developmental arrest or prevents isp-1 animals from reaching adulthood, indicating a stage-specific requirement. (pqac-00000032, pqac-00000033, pqac-00000035, pqac-00000036, pqac-00000038) | Bennett et al., 2014; Wu et al., 2018 (pqac-00000032, pqac-00000033, pqac-00000035, pqac-00000036, pqac-00000038) |
| Developmental timing (L3/L4 window) | Required for establishment of lifespan extension | ETC inhibition including isp-1 RNAi extends lifespan only when imposed during larval development, especially by late L3/early L4; similar perturbation in adults fails to produce longevity, indicating a developmentally programmed mitochondrial checkpoint or signaling window. (pqac-00000053, pqac-00000054, pqac-00000055, pqac-00000056) | Rea et al., 2007 (pqac-00000053, pqac-00000054, pqac-00000055, pqac-00000056) |


*Table: This table summarizes the major signaling pathways and timing requirements linked to isp-1-mediated mitochondrial dysfunction in C. elegans. It distinguishes pathways needed for lifespan extension from those primarily required for development.*