Abstract
The m-AAA protease preserves proteostasis of the inner mitochondrial membrane. It ensures a functional respiratory chain, by controlling the turnover of respiratory complex subunits and allowing mitochondrial translation, but other functions in mitochondria are conceivable. Mutations in genes encoding subunits of the m-AAA protease have been linked to various neurodegenerative diseases in humans, such as hereditary spastic paraplegia and spinocerebellar ataxia. While essential functions of the m-AAA protease for neuronal survival have been established, its role in adult glial cells remains enigmatic. Here, we show that deletion of the highly expressed subunit AFG3L2 in mature mouse oligodendrocytes provokes early-on mitochondrial fragmentation and swelling, as previously shown in neurons, but causes only late-onset motor defects and myelin abnormalities. In contrast, total ablation of the m-AAA protease, by deleting both Afg3l2 and its paralogue Afg3l1, triggers progressive motor dysfunction and demyelination, owing to rapid oligodendrocyte cell death. Surprisingly, the mice showed premature hair greying, caused by progressive loss of melanoblasts that share a common developmental origin with Schwann cells and are targeted in our experiments. Thus, while both neurons and glial cells are dependant on the m-AAA protease for survival in vivo, complete ablation of the complex is necessary to trigger death of oligodendrocytes, hinting to cell-autonomous thresholds of vulnerability to m-AAA protease deficiency.
Highlights
Oligodendrocytes are glial cells of the central nervous system (CNS) that produce myelin to enhance conduction velocity
Myelin production is extremely costly from the energetic point of view, and oligodendrocytes that are synthesizing myelin are susceptible to mitochondrial dysfunction
We show that oligodendrocytes are capable to cope with reduced levels of the complex, but undergo rapid death upon complete ablation of the m-AAA protease
Summary
Oligodendrocytes are glial cells of the central nervous system (CNS) that produce myelin to enhance conduction velocity. It has been hypothesized that post-myelination oligodendrocytes can undergo a metabolic switch to glycolysis, and provide metabolic support to axons, by supplying lactate as an energy source [2, 4] In support of this hypothesis, oligodendrocyte-specific deletion of an essential assembly factor for complex IV, Cox, did not lead to axonal degeneration or demyelination [2], strongly suggesting that these cells can survive a respiratory chain deficiency. The m-AAA protease is a large proteolytic complex in the inner mitochondrial membrane endowed with crucial and pleiotropic roles in mitochondria It regulates the turnover of respiratory chain subunits [6,7,8], controls ribosome assembly and thereby mitochondrial translation [9, 10], and affects mitochondrial dynamics [11]. The mouse genome contains a third gene, encoding a functional m-AAA protease subunit, Afg3l1, which can form either homo-oligomers or hetero-oligomers with AFG3L2 or paraplegin [12]
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