Journal article

Mitochondrial matrix proteostasis is linked to hereditary paraganglioma: LON-mediated turnover of the human flavinylation factor SDH5 is regulated by its interaction with SDHA

Ayenachew Bezawork-Geleta, Tamanna Saiyed, David A Dougan, Kaye N Truscott

The FASEB Journal | FEDERATION AMER SOC EXP BIOL | Published : 2014


Mutations in succinate dehydrogenase (SDH) subunits and assembly factors cause a range of clinical conditions. One such condition, hereditary paraganglioma 2 (PGL2), is caused by a G78R mutation in the assembly factor SDH5. Although SDH5(G78R) is deficient in its ability to promote SDHA flavinylation, it has remained unclear whether impairment to its import, structure, or stability contributes to its loss of function. Using import-chase analysis in human mitochondria isolated from HeLa cells, we found that the import and maturation of human SDH5(G78R) was normal, while its stability was reduced significantly, with ~25% of the protein remaining after 180 min compared to ~85% for the wild-type..

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Awarded by Australian Research Council

Funding Acknowledgements

This work was supported by Australian Research Council fellowships to D.A.D (DP110103936) and K.N.T. (FT0992033), a La Trobe University postgraduate research scholarship to A.B-G., and a Cooperative Research Centre postgraduate award to T.S. Protein sequencing was performed by the Australian Proteome Analysis Facility (North Ryde, NSW, Australia). The authors thank N. Hoogenraad and M. Ryan (La Trobe University) for anti-HSP60 and anti-NDUFA9 antisera, respectively.