Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

Abstract

Disturbances in the morphology and function of mitochondria cause neurological diseases, which can affect the central and peripheral nervous system. The i‐AAA protease YME1L ensures mitochondrial proteostasis and regulates mitochondrial dynamics by processing of the dynamin‐like GTPase OPA1. Mutations in YME1L cause a multi‐systemic mitochondriopathy associated with neurological dysfunction and mitochondrial fragmentation but pathogenic mechanisms remained enigmatic. Here, we report on striking cell‐type‐specific defects in mice lacking YME1L in the nervous system. YME1L‐deficient mice manifest ocular dysfunction with microphthalmia and cataracts and develop deficiencies in locomotor activity due to specific degeneration of spinal cord axons, which relay proprioceptive signals from the hind limbs to the cerebellum. Mitochondrial fragmentation occurs throughout the nervous system and does not correlate with the degenerative phenotype. Deletion of Oma1 restores tubular mitochondria but deteriorates axonal degeneration in the absence of YME1L, demonstrating that impaired mitochondrial proteostasis rather than mitochondrial fragmentation causes the observed neurological defects.

Mitochondria-ER contacts in reactive astrocytes coordinate local perivascular domains to promote vascular remodelling

“…Yet, induction of mitochondrial enrichment via AAV-linker expression alone in Mfn2 cKO mice was sufficient to restore a normal vascular density, despite partial astrocytic OXPHOS dysfunction. Also, while astrocyte-specific Yme1l deletion reproduced most of the mitochondrial and vascular phenotypes identified in Mfn2 cKO mice, CNSspecific Yme1l knock-out mice show only a mild OXPHOS deficiency (Sprenger et al, 2019), suggesting that alterations in astrocyte mitochondrial respiration per se may not be the leading cause for the lack of vascular repair. One intriguing possibility, however, is that this close apposition to the BBB of a dense supply of mitochondria in control astrocytes may favour either the local release of specific signalling molecules or contribute to generate locally a chronic metabolic environment (Al-Mehdi et al, 2012;Lopez-Fabuel et al, 2016), which may act non cellautonomously in assisting the angiogenic response during the days that follow the initial insult (Wong et al, 2017).…”

“…To understand if the vascular phenotype identified in Mfn2 cKO mice was MFN2-specific, we performed the same experiments in a third conditional mouse model in which mitochondrial fusion was also visibly impaired. We utilized astrocyte-specific Yme1l cKO mice, in which deletion of the mitochondrial i-AAA protease Yme1l disrupts the proteolytic processing of the inner membrane GTPase OPA1, leading to a marked mitochondrial fragmentation in cells (Anand et al, 2014) but only minor and late-onset OXPHOS deficiency (Sprenger et al, 2019). Similar to Mfn2 cKO astrocytes, Yme1l cKO astrocytes displayed a conspicuous fragmentation of their mitochondrial network in vivo (Supp Fig 6B).…”

Mitochondrial Mechanisms of Neuromuscular Junction Degeneration with Aging

“…Thus, alterations in m-AAA proteases could play a role in the accumulation of mitochondria having undergone permeability transition in the motoneuron terminals of aged rats [47]. Similarly, loss of the AAA+ protease YME1L, which not only degrades damaged or non-assembled proteins in the mitochondrial inner membrane but also cleaves Opa1 to activate it and catalyze inner membrane fusion [93], causes ocular degeneration and axonal degeneration in the spinal cord [94]. The potential role of alterations in function of AAA+ proteases in muscle and motoneuron mitochondrial impairment with aging is unknown, but is worthy of consideration based upon the aforementioned effects.…”

Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

“…The m-AAA protease exposes its catalytic domain to the matrix, while the catalytic domain of the i-AAA protease faces the intermembrane space. These proteases degrade misfolded proteins of the inner membrane, being their substrate specificity mainly depending on the topology of the respective substrates (Leonhard et al, 2000;Almajan et al, 2012;Stiburek et al, 2012;Anand et al, 2014;Kondadi et al, 2014;König et al, 2016;Wai et al, 2016;Wang et al, 2016;Pareek et al, 2018;Sprenger et al, 2019). In the inner mitochondrial membrane space, misfolded and damaged proteins are degraded by the proteases Omi/HtrA2 and Atp23 (Osman et al, 2007;Clausen et al, 2011).…”