Structural basis of mitochondrial inner membrane shape and dynamic

Objetivo

Here, I propose to study the structure and mechanisms of the cellular machineries mediating the shape and dynamics of the mitochondrial inner membrane (IM). The mitochondrial IM contains membrane invaginations called cristae. These are connected by tubular openings, the crista junctions, to the remaining IM. Mitochondrial shape constantly changes due to membrane fission and fusion events, and a balance of both processes is required for proper functioning of mitochondria. Abnormal mitochondrial shape and altered dynamics are associated with severe diseases, such as cancer and neurodegeneration.
Sourcing my group’s expertise in dynamin superfamily GTPases, I wish to understand the molecular mechanisms of how OPA1 can achieve mitochondrial IM fusion and cristae formation. To this end, the X-ray crystallographic structure of OPA1 will be determined and complemented by a comprehensive biochemical characterization. Cell-based assays will be employed to decipher the exact mechanism by which OPA1 carries out its two functions and how specific mutations in OPA1 disturb these processes and, thereby, induce human disease.
The multiprotein MINOS complex was recently shown to be involved in the formation of crista junctions. I propose to explore the architecture of the MINOS complex. To this end, X-ray crystallographic structures of single components, subcomplexes and, eventually, the complete complex will be determined. Based on these structures, the mechanism of MINOS in mitochondrial membrane remodeling and crista junction formation will be dissected using a structure-based mutagenesis approach.
Components of MINOS were shown to interact with OPA1 and with the sorting and assembly machinery (SAM) of the outer mitochondrial membrane. The interactions of MINOS with OPA1 and SAM will be biochemically mapped and structurally characterized. To understand their functions, the effect of disrupting mutations on crista junction formation and mitochondrial dynamics will be explored.

Ámbito científico

Régimen de financiación

ERC-CG - ERC Consolidator Grants

Coordinador

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)

Dirección

Robert rossle strasse 10
13125 Berlin
Alemania

Región

Berlin Berlin Berlin

Tipo de actividad

Research Organisations

Contacto administrativo

Ioannis Legouras (Dr.)

Investigador principal

Oliver Daumke (Prof.)

Enlaces

Contactar con la organización Sitio web

Aportación de la UE

Sin datos

Beneficiarios (1)

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)

Alemania

Aportación de la UE

€ 1 999 972,20