Abstract
Mitochondria are organelles that are present in all nucleated cells in the body. They have manifold functions but famously generate ATP efficiently through the process of oxidative phosphorylation. This ensures all tissues have an adequate energy supply and underlines the need for a fully functional mitochondrial network. Since mitochondrial biogenesis and maintenance require components from two genetic sources, mitochondrial diseases can result from mutations in either the nuclear or the mitochondrial genome (mtDNA). Enigmatically, mitochondrial disease can affect individuals at any age and in any tissue (Lightowlers et al , 2015). For a subset of mutations, the genotype can be ascribed to a clinical phenotype and a number of mutations are associated with remarkable tissue selectivity (Boczonadi et al , 2018). However, the gene expression pathways governing this tissue‐specific presentation are far from clear. In this issue of EMBO Molecular Medicine , Sprenger et al (2018) use mouse models to investigate the consequences of deleting a mitochondrial protease, YME1L, in neuronal/glial precursors. The loss causes multiple defects at both cell and tissue level, including a marked fragmentation of the mitochondrial network. Tandem depletion of a second mitochondrial protease, Oma1, successfully restored the mitochondrial connectivity, but did not rescue the ocular defects and caused an earlier onset of neurological dysfunction. Thus, in addition to other findings, the authors conclude that a fragmented mitochondrial network contributes less to the disease phenotype than the disruption of mitochondrial proteostasis.
Highlights
Mitochondria are organelles that are present in all nucleated cells in the body
This is explained by the stress-activated cleavage of the long isoform of Opa1 (LOpa1) by a different protease, Oma1, in the Yme1l knockout mouse model
Fragmented mitochondrial networks can be associated with defects in oxidative phosphorylation, loss of Yme1l in mice caused disrupted mitochondrial morphology and neurological defects independently of any significant deficits in oxidative phosphorylation
Summary
Mitochondria are organelles that are present in all nucleated cells in the body They have manifold functions but famously generate ATP efficiently through the process of oxidative phosphorylation. The gene expression pathways governing this tissue-specific presentation are far from clear In this issue of EMBO Molecular Medicine, Sprenger et al (2018) use mouse models to investigate the consequences of deleting a mitochondrial protease, YME1L, in neuronal/glial precursors. The use of mouse models to address such questions can be very informative This approach has been adopted by the Langer laboratory to investigate the molecular consequences of mutations in the mitochondrial i-AAA protease, YME1L. The latter is an enzyme that is responsible for the homeostasis both of mitochondrial proteins and phospholipids.
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