Mechanism of assembly of mitochondrial respiratory complex II

• Thesis title in Czech: Mechanismus asemblace mitochondriálního respiračního komplexu II
• Thesis title in English: Mechanism of assembly of mitochondrial respiratory complex II
• Key words: mitochondrie, respirace, elektronový transferový řetězec, respirační complex II, asemblace
• English key words: mitochondria, respiration, electron transfer chain, respiratory complex II, assembly
• Academic year of topic announcement: 2025/2026
• Thesis type: dissertation
• Thesis language: angličtina
• Department: Department of Physiology (31-152)
• Supervisor: prof. Ing. Jiří Neužil, CSc.

Preliminary scope of work

Náš výzkum se soustředí na biochemii a funkci mitochondriálního respiračního komplexu II (CII; take zvaný sukcinát dehydrogenáza, SDH), neboť jsme identifikovali CII jako nový cíl protirakovinné léčby¹ a také jsme zjistili, že se CII hromadí v buňkách za určitých podmínek jako subcomplex II zvaný CII_low.² Nedávno jsme s kolegy z University of California in San Francisco a Vanderbilt University popsali roli asemblačních faktorů (AFs) CII při maturaci katalytické podjednotky CII, SDHA,³ což se zdá být kritické pro asemblaci CII (sestavajícího z podjednotek SDHA, SDHB, SDHC a SDHD a ze 4 AFs). V tomto projektu budeme studovat kroky asemblace CII po maturaci SDH, vedoucí k tvorbě plně asemblovaného a aktivního CII. Budeme používat geneticky upravenou linii hPheo1, která napomůže charakterizovat, jak maturují podjednotky SDHB, SDHC a SDHD a jaká je role SDHAF1 a SDHAF3. Tyto buňky jsou připravené z pacienta s feochromocytomem, což je typ nádoru charakteristický častými aberacemi v podjednotkách a AFs CII. Tento projekt přispěje nejen k pochopení asemblace CII, ale také ukáže na roli aberací v podjednotkách CII a AFs v tvorbě nádorů v myším modelu. Jelikož CII je na ‘křižovatce’ Krebsova cyklu a oxidativní fosforylace,⁴ tento project take ukáže na roli CII v mitochondriálním metabolism a bioenergetice.
1. Dong LF et al (2008) a-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene 27, 4324-4335.
2. Bezawork-Geleta A et al (2018) Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints. Nat Commun 9, 2221.
3. Sharma P et al (2023) Intrinsic disorder regulates stepwise complex II biogenesis. Nat Commun, in press.
4. Bezawork-Geleta A et al (2017) Mitochondrial complex II: At the crossroads. Trends Biochem Sci 42, 312-325.

Preliminary scope of work in English

Our research has been focused on the biochemistry and function of mitochondrial respiratory complex II (CII; also referred to as succinate dehydrogenase, SDH), since we identified it earlier as a novel target for cancer therapy,¹ and since we discovered a sub-complex II, referred to as CII_low, that accumulates under certain conditions.² Recently, with collaborators form the University of California in San Francisco and Vanderbilt University we have reported sequential role of SDH assembly factors (AFs) in maturation of the CII catalytic subunit SDHA,³ which appears to be critical for assembly of CII comprising 4 subunits (SDHA, SDHB, SDHC and SDHD) and 4 AFs. In this project we will delineate the steps of CII assembly following SDHA maturation, leading to fully assembled and functional CII. We will use genetically engineered cell line hPheo1, providing a cellular tool to understand how subunits SDHB, SDHC and SDHD mature and associate with mature SDHA subunit, and what is the role of SDHAF1 and SDHAF3. hPheo1 cells are derived from a patient with endocrine tumour (PHEO), typified by frequent aberrations in subunits and AFs of CII. We will not only delineate assembly of CII but will also study how aberrations in its subunits and AFs affect tumour formation in a mouse model. Since CII is at the crossroads of the Krebs cycle and oxidative phosphorylation,⁴ understanding its assembly and function will also help uncover how this complex affects mitochondrial metabolism/bioenergetics.
1. Dong LF et al (2008) a-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene 27, 4324-4335.
2. Bezawork-Geleta A et al (2018) Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints. Nat Commun 9, 2221.
3. Sharma P et al (2023) Intrinsic disorder regulates stepwise complex II biogenesis. Nat Commun, in press.
4. Bezawork-Geleta A et al (2017) Mitochondrial complex II: At the crossroads. Trends Biochem Sci 42, 312-325.