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Mitochondrial Complex II (CII) activity supports multiple types of respiration and connects metabolic state with succinate signaling. It is therefore unsurprising that CII activity has been linked to biological phenomena that require crosstalk between metabolism and signaling, including neurodegeneration, metabolic shifts in cancer, immune activation, and ischemia reperfusion injury. In each of these processes, CII activity may be regulated at the level of assembly, with the disassembled SDHA subunit stored as metastable species with one or more assembly factors. However, both the exact molecular nature of these species and the mechanism of release of SDHA from these metastable species is unclear. In this work, we identified that transfer of SDHA into CII proceeds through at least three metastable intermediates, we assigned the sequence of appearance of these intermediates, and we determined structures for two of these. A complex between SDHA and one of its assembly factors, succinate dehydrogenase assembly factor 2 (SDHAF2), is likely the main alternative species that accumulates in cells. A second assembly factor, succinate dehydrogenase assembly factor 4 (SDHAF4), must displace SDHAF2 for assembly to proceed. Changes in intrinsic disorder in both SDHAF2 and SDHAF4 are required to release SDHA from the metastable complexes. Evaluation of unrelated biological complexes suggests that changes in disorder may guide post-folding biogenesis during both self-assembly and assisted assembly. |
