Depletion of respiratory chain complexes modulates cristae architecture via MIC10 in human cells

by Kateryna Yarova
Doctoral thesis
Date of Examination:2024-10-02
Date of issue:2024-10-18
Advisor:Prof. Dr. Stefan Jakobs
Referee:Prof. Dr. Stefan Jakobs
Referee:Prof. Dr. Michael Thumm
Persistent Address: http://dx.doi.org/10.53846/goediss-10809

 

 

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Abstract

English

The complex structure of the inner mitochondrial membrane plays a key role in mitochondrial function. The inner mitochondrial membrane is divided into the inner boundary membrane and the cristae membrane, which is characterized by pleomorphic invaginations. The cristae membranes are the main site of oxidative phosphorylation (OXPHOS) as they harbor the complexes involved in cellular respiration, including complexes I-IV of the mitochondrial respiratory chain and ATP synthase. Although the function of F1F0-ATP synthase in stabilizing the cristae rims has been well studied, it remains to be elucidated how the respiratory chain complexes, whose absence often disrupts cristae morphology and leads to severe metabolic diseases, can influence the lamellar morphology of the cristae. To elucidate the potential influence of respiratory chain complexes on the inner mitochondrial membrane, I investigated the recently identified mitochondrial translation factor FAM210A, which has been implicated in mitochondrial inner membrane remodeling. Using CRISPR-Cas9 gene editing, I was able to show that the absence of the FAM210A protein leads to a reduction in the abundance of respiratory chain complexes (RCC). This reduction in RCC leads to the down-regulation of MIC10 from MICOS, affecting the morphology of the inner mitochondrial membrane. Reintroduction of MIC10 into the respiratory chain complex-depleted system restores the wild-type lamellar cristae membrane phenotype, but not mitochondrial respiratory function. In summary, I have elucidated the role of the protein FAM210A as a translational factor in HeLa cells and investigated various functional aspects. I have discovered a previously unknown interdependency between RCC and mitochondrial inner membrane structure mediated by MIC10 human cells. I propose a new regulatory axis in which respiratory chain complexes regulate the abundance of MIC10 and thereby adapt the architecture of the cristae.
Keywords: inner mitochondrial membrane; respiratory chain complexes; MICOS complex; cristae membrane; mitochondrial morphology; oxidative phosphorylation