Periodic Reporting for period 1 - CICURE (Increasing complex I stability as a cure for mitochondrial diseases)
Reporting period: 2018-08-01 to 2020-01-31
One of the main tasks of mitochondria is the constant supply of the cell with energy; hence they are named power plants of the cell. If this supply is no longer guaranteed due to disturbances in signaling processes, this has serious consequences for the entire organism and diseases occurs. The power plant machine in the mitochondria consists of five respiratory chain complexes I - V. Through them, the food we eat is ultimately converted into usable energy. Complex I is the main entry point into respiratory chain and the biggest complex inside mitochondria. Thus, it is not surprising that CI deficiency is the most common pathology connected with respiratory chain deficiency implicated in the pathogenesis of mitochondrial diseases, Parkinsonism, diabetes, cancer, and aging. Through CICURE project we unravelled the very first mechanism for the maintenance of CI, by which mitochondrial matrix protease CLPP selectively turns over damaged CI subunits. This CI salvage pathway preserves highly functional CI through a favourable mechanism that demands much lower energetic cost than de novo synthesis and reassembly of the entire CI. This pathway also acts as a safety valve for the cell, directly prevent harmful reactive oxygen species (ROS) from being produced and released in the power plant engine.
In addition to the general novelty of the entire mechanism, we were learn to learn that it is often better for the organism to keep some respiratory chain machines running despite damage instead of dismantling them completely. We showed that diminished turnover of the catalytic part of CI could delay and slowdown the disassembly of the whole CI, resulting in an improved phenotype. However, the beneficial effect does not necessarily originate from the restored CI activity. Instead, we propose that positive outcome might be the result of the stabilization of mitochondrial internal structures. Alternatively, presence of functional free CI components might provide means to maintain metabolites even when CI is not functioning properly, leading to better redox fitness and lower ROS production. In future, we would like to investigate further just how far-reaching and versatile the molecular pathway that have discovered is, especially trying to recognize the full potential for possible disease therapies.
In addition to the general novelty of the entire mechanism, we were learn to learn that it is often better for the organism to keep some respiratory chain machines running despite damage instead of dismantling them completely. We showed that diminished turnover of the catalytic part of CI could delay and slowdown the disassembly of the whole CI, resulting in an improved phenotype. However, the beneficial effect does not necessarily originate from the restored CI activity. Instead, we propose that positive outcome might be the result of the stabilization of mitochondrial internal structures. Alternatively, presence of functional free CI components might provide means to maintain metabolites even when CI is not functioning properly, leading to better redox fitness and lower ROS production. In future, we would like to investigate further just how far-reaching and versatile the molecular pathway that have discovered is, especially trying to recognize the full potential for possible disease therapies.