The Influence of the PD-associated Gene Products PINK1 and HtrA2/Omi on Mitochondrial Integrity

Abstract

Mitochondria have been implicated in Parkinson’s disease (PD) since the discovery that mitochondrial complex I inhibitors cause parkinsonian symptoms. The more recent discovery of mitochondria localised PD-associated genes has further fuelled the interest in uncovering the role of mitochondria in the progression of the disease. This study has investigated mitochondrial parameters, mainly in loss-of-function models of two of these genes, namely PINK1 and HtrA2/Omi.

PINK1 could be shown to localise to both the cytosol and mitochondria. Further investigation of mitochondrial integrity revealed a loss of mitochondrial inner membrane potential in cells lacking PINK1. A loss of mitochondrial integrity would render not just the mitochondria, but the whole cell more susceptible to cell death.

Using a mouse embryonic fibroblast cell culture model from HtrA2/Omi knock-out mice, the necessity of the protein under physiological conditions was assessed. Loss of HtrA2/Omi leads to a decrease in mitochondrial membrane potential, as well as increased ROS and ATP levels. Most interestingly, HtrA2/Omi was further found to modulate mitochondrial morphology in a protease dependent fashion. Cells lacking HtrA2/Omi show elongated mitochondria, which can be rescued by over-expression of wild-type but not a protease dead form of HtrA2/Omi. The elongated mitochondrial phenotype coincides with ultrastructural alterations in the mitochondria. These cells also display increased levels of easily extractable OPA1, a protein known to be involved in mitochondrial inner membrane fusion and the maintenance of mitochondrial cristae structures. As a final point, it could be shown that HtrA2/Omi is protective against both proteasomal and chronic oxidative stress, possibly through the regulation of the PI3K/Akt signaling pathway, as HtrA2/Omi was shown to influence Akt activation.

In brief, PINK1 and HtrA2/Omi were shown to be essential for mitochondrial integrity under physiological conditions. The loss of HtrA2/Omi further affects mitochondrial morphology, possibly through modulation of OPA1. Finally, HtrA2/Omi is protective under certain stress conditions.

Seit dem es bekannt wurde, dass die Hemmung des mitochondrialen Komplexes I zu Parkinson-ähnlichen Symptomen führt, wurden die Mitochondrien mit Morbus Parkinson (PD) in Verbindung gebracht. Desweiteren konnten viele Gene mit PD verknüpft werden, deren Proteine Funktionen in den Mitochondrien haben oder Auswirkungen auf diese haben. Die vorliegende Arbeit analysiert die mitochondrialen Funktionen von PINK1 und HtrA2/Omi in Zellkultur-Modellen. Zusammenfassend konnte gezeigt werden, dass PINK1 und HtrA2/Omi wichtig für die Erhaltung der mitochondrialen Integrität unter physiologischen Bedingungen sind. Außerdem beeinflusst der Verlust von HtrA2/Omi die mitochondriale Morphologie, möglicherweise durch die Beeinflussung des mitochondrialen Fusionsproteins OPA1. Abschließend konnte gezeigt werden, dass HtrA2/Omi protektiv gegen Stress wirken kann.