MiPsummer Programme pdf - Mitochondrial Physiology Society

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Abstract # 14
MITOCHONDRIAL RHOMBOID PARL AS A CRITICAL REGULATOR OF CELL
DEATH
Marco Spinazzi, 1 Sara Cipolat, 2 Tomasz Rudka, 1 Dieter Hartmann, 1 Veronica Costa, 2 Lutgarde
Serneels, 1 Katleen Craessaerts, 1 Kristine Metzger, 1 Christian Frezza, 2 Wim Annaert, 3 Luciano
D’Adamio, 5 Carmen Derks, 1 Tim Dejaegere, 1 Luca Pellegrini, 6 Rudi D’Hooge, 4 Luca Scorrano, 2 and
Bart De Strooper 1
1
Laboratory for the Research of Neurodegenerative Diseases, Center for Human Genetics, Flanders
Interuniversity Institute for Biotechnology (VIB4) and K.U.Leuven, Leuven, Belgium
2 Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy
3 Membrane Trafficking Laboratory
4 Laboratory of Biological Psychology, K.U.Leuven, Leuven, Belgium
5
Albert Einstein College of Medicine, Bronx, NY 10461, USA
6 Centre de Recherche Robert Giffard, Universite` Laval, G1J 2G3 Quebec, Ca
Background: PARL is a mitochondrial serine protease belonging to the large family of rhomboid
intramembrane proteases with an unknown function in the mitochondrion.
Objectives: to define the clinical, pathological, and biochemical phenotype of the Parl -/- mice, and
of the conditional knock out Parl nestincre-/- .
Methods: Parl -/- mice were obtained using a PGK-driven Cre-recombinase. Animals carrying a
null allele in the brain (Parl nestincre-/- ) were obtained by breeding with transgenic females expressing
a Nestin-driven Cre-recombinase. Apoptosis was evaluated through TUNEL staining in cells and
tissues. Mitochondrial respiration was evaluated in isolated mitochondria from MEF using a Clarketype
electrode. Mitochondrial morphology was evaluated by confocal microscopy in MEF
transfected with mtYFP.
Results: Parl -/- mice show a striking multisystem disorder with generalized cachexia, atrophy of
thymus and spleen and early death before the age of 3 months. Increased apoptosis is detected in the
immune system, and cultured cells are more vulnerable to release cytochrome c after challenge with
intrinsic apoptotic inducers, implicating PARL as an important regulator of cell death. Surprisingly,
oxygen consumption measurements on isolated mitochondria from MEF are normal, and Parl -/-
cells did not show alterations in mitochondrial morphology or fusion rates.
Conclusions: PARL is indispensable for life. Deletion of PARL leads to increased susceptibility to
apoptotic stimuli through mechanism which warrant further evaluations.