Spinazzi, M;
Radaelli, E;
Horré, K;
Arranz, AM;
Gounko, NV;
Agostinis, P;
Maia, TM;
... De Strooper, B; + view all
(2019)
PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome.
Proceedings of the National Academy of Sciences (PNAS)
, 116
(1)
pp. 277-286.
10.1073/pnas.1811938116.
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Abstract
The mitochondrial intramembrane rhomboid protease PARL has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that Parl ablation in mouse causes a necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with conditional PARL deficiency in the nervous system, but not in muscle, develop a similar phenotype as germline Parl KOs, demonstrating the vital role of PARL in neurological homeostasis. Genetic modification of two major PARL substrates, PINK1 and PGAM5, do not modify this severe neurological phenotype. Parl-/- brain mitochondria are affected by progressive ultrastructural changes and by defects in Complex III (CIII) activity, coenzyme Q (CoQ) biosynthesis, and mitochondrial calcium metabolism. PARL is necessary for the stable expression of TTC19, which is required for CIII activity, and of COQ4, which is essential in CoQ biosynthesis. Thus, PARL plays a previously overlooked constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and structural abnormalities leading to neuronal necrosis and Leigh-like syndrome.
| Type: | Article |
|---|---|
| Title: | PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.1811938116 |
| Publisher version: | https://doi.org/10.1073/pnas.1811938116 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Leigh syndrome, mitochondria, neurodegeneration, respiratory chain, rhomboid protease |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10066652 |
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