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Thomas Langer – One of the best experts on this subject based on the ideXlab platform.

  • Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration.
    Glia, 2019
    Co-Authors: Sara Murru, Esther Barth, Thomas Langer, Simon Hess, Eva R. Almajan, Désirée Schatton, Steffen Hermans, Susanne Brodesser, Peter Kloppenburg, Elena I. Rugarli
    Abstract:

    Mitochondrial dysfunction causes neurodegeneration but whether impairment of mitochondrial homeostasis in astrocytes contributes to this pathological process remains largely unknown. The m-AAA protease exerts quality control and regulatory functions crucial for mitochondrial homeostasis. AFG3L2, which encodes one of the subunits of the m-AAA protease, is mutated in spinocerebellar ataxia SCA28 and in infantile syndromes characterized by spastic-ataxia, epilepsy and premature death. Here, we investigate the role of AFG3L2 and its redundant homologue Afg3l1 in the Bergmann glia (BG), radial astrocytes of the cerebellum that have functional connections with Purkinje cells (PC) and regulate glutamate homeostasis. We show that astrocyte-specific deletion of AFG3L2 in the mouse leads to late-onset motor impairment and to degeneration of BG, which display aberrant morphology, altered expression of the glutamate transporter EAAT2, and a reactive inflammatory signature. The neurological and glial phenotypes are drastically exacerbated when astrocytes lack both Afg31l and AFG3L2, and therefore, are totally depleted of the m-AAA protease. Moreover, mitochondrial stress responses and necroptotic markers are induced in the cerebellum. In both mouse models, targeted BG show a fragmented mitochondrial network and loss of mitochondrial cristae, but no signs of respiratory dysfunction. Importantly, astrocyte-specific deficiency of Afg3l1 and AFG3L2 triggers secondary morphological degeneration and electrophysiological changes in PCs, thus demonstrating a non-cell-autonomous role of glia in neurodegeneration. We propose that astrocyte dysfunction amplifies both neuroinflammation and glutamate excitotoxicity in patients carrying mutations in AFG3L2, leading to a vicious circle that contributes to neuronal death.

  • m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration
    Cell Research, 2018
    Co-Authors: Maria Patron, Hans-georg Sprenger, Thomas Langer
    Abstract:

    The function of mitochondria depends on ubiquitously expressed and evolutionary conserved m -AAA proteases in the inner membrane. These ATP-dependent peptidases form hexameric complexes built up of homologous subunits. AFG3L2 subunits assemble either into homo-oligomeric isoenzymes or with SPG7 (paraplegin) subunits into hetero-oligomeric proteolytic complexes. Mutations in AFG3L2 are associated with dominant spinocerebellar ataxia (SCA28) characterized by the loss of Purkinje cells, whereas mutations in SPG7 cause a recessive form of hereditary spastic paraplegia (HSP7) with motor neurons of the cortico-spinal tract being predominantly affected. Pleiotropic functions have been assigned to m -AAA proteases, which act as quality control and regulatory enzyenzymes in mitochondria. Loss of m -AAA proteases affects mitochondrial protprotein synthesis and respiration and leads to mitochondrial fragmentation and deficiencies in the axonal transport of mitochondria. Moreover m -AAA proteases regulate the assembly of the m itochondrial c alcium u niporter (MCU) complex. Impaired degradation of the MCU subunit EMRE in AFG3L2-deficient mitochondria results in the formation of deregulated MCU complexes, increased mitochondrial calcium uptake and increased vulnerability of neurons for calcium-induced cell death. A reduction of calcium influx into the cytosol of Purkinje cells rescues ataxia in an AFG3L2-deficient mouse model. In this review, we discuss the relationship between the m -AAA protease and mitochondrial calcium homeostasis and its relevance for neurodegeneration and describe a novel mouse model lacking MCU specifically in Purkinje cells. Our results pledge for a novel view on m -AAA proteases that integrates their pleiotropic functions in mitochondria to explain the pathogenesis of associated neurodegenerative disorders.

  • The Mitochondrial m-AAA Protease Prevents Demyelination and Hair Greying
    PLoS Genetics, 2016
    Co-Authors: Shuaiyu Wang, Julie Jacquemyn, Sara Murru, Paola Martinelli, Esther Barth, Thomas Langer, Carien M. Niessen, Elena I. Rugarli
    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.

Giorgio Casari – One of the best experts on this subject based on the ideXlab platform.

  • Upregulation of Peroxiredoxin 3 Protects AFG3L2-KO Cortical Neurons In Vitro from Oxidative Stress: A Paradigm for Neuronal Cell Survival under Neurodegenerative Conditions.
    Oxidative medicine and cellular longevity, 2019
    Co-Authors: Barbara Bettegazzi, Giorgio Casari, Francesca Maltecca, Fabio Grohovaz, Daniele Zacchetti, Ilaria Pelizzoni, Floramarida Salerno Scarzella, Lisa Michelle Restelli, Franca Codazzi
    Abstract:

    Several neurodegenerative disorders exhibit selective vulnerability, with subsets of neurons more affected than others, possibly because of the high expression of an altered gene or the presence of particular features that make them more susceptible to insults. On the other hand, resilient neurons may display the ability to develop antioxidant defenses, particularly in diseases of mitochondrial origin, where oxidative stress might contribute to the neurodegenerative process. In this work, we investigated the oxidative stress response of embryonic fibroblasts and cortical neurons obtained from AFG3L2-KO mice. AFG3L2 encodes a subunit of a protease complex that is expressed in mitochondria and acts as both quality control and regulatory enzyme affecting respiration and mitochondrial dynamics. When cells were subjected to an acute oxidative stress protocol, the survival of AFG3L2-KO MEFs was not significantly influenced and was comparable to that of WT; however, the basal level of the antioxidant molecule glutathione was higher. Indeed, glutathione depletion strongly affected the viability of KO, but not of WT MEF, thereby indicating that oxidative stress is more elevated in KO MEF even though well controlled by glutathione. On the other hand, when cortical KO neurons were put in culture, they immediately appeared more vulnerable than WT to the acute oxidative stress condition, but after few days in vitro, the situation was reversed with KO neurons being more resistant than WT to acute stress. This compensatory, protective competence was not due to the upregulation of glutathione, rather of two mitochondrial antioxidant proteins: superoxide dismutase 2 and, at an even higher level, peroxiredoxin 3. This body of evidence sheds light on the capability of neurons to activate neuroprotective pathways and points the attention to peroxiredoxin 3, an antioxidant enzyme that might be critical for neuronal survival also in other disorders affecting mitochondria.

  • m-AAA and i-AAA complexes coordinate to regulate OMA1, the stress-activated supervisor of mitochondrial dynamics.
    Journal of cell science, 2018
    Co-Authors: Francesco Consolato, Francesca Maltecca, Susanna Tulli, Irene Sambri, Giorgio Casari
    Abstract:

    The proteolytic processing of dynamin like GTPase OPA1, mediated by the activity of both YME1L1 ( i- AAA protease complex) and OMA1, is a crucial step in the regulation of mitochondrial dynamics. OMA1 is a zinc metallopeptidase of the inner mitochondrial membrane that undergoes pre-activating proteolytic and auto-proteolytic cleavage after mitochondrial import. Here, we identify AFG3L2 ( m- AAA complex) as the major protease mediating this event by maturing the pre-pro-OMA1 of 60 kDa to the pro-OMA1 form of 40 kDa by severing the amino-terminal part without recognizing specific consensus sequence. Therefore, m- AAA and i- AAA complexes coordinately regulate OMA1 processing and turnover, and consequently OPA1 isoforms, thus adding new information in the comprehension of the molecular mechanisms in mitochondrial dynamics and of neurodegenerative diseases affected by these phenomena.

  • ROLE OF MITOCHONDRIA IN CORTICAL NEURONS FROM SPINOCEREBELLAR ATAXIA 28 (SCA28) MOUSE MODEL.
    Journal of World Mitochondria Society, 2015
    Co-Authors: Franca Codazzi, Giorgio Casari, Francesca Maltecca, Floramarida Salerno, Federico Zucca, Barbara Bettegazzi, Daniele Zacchetti, Fabio Grohovaz
    Abstract:

    In this study we investigated the role of mitochondria in cortical neurons obtained from a mouse model of spinocerebellar ataxia 28 (SCA28) characterized by dark degeneration of Purkinje cells. Primary cortical neurons from mice, WT and KO for AFG3L2 (the mitochondrial gene mutated in SCA28), were analyzed by single-cell videomicroscopy after iron overload, a condition able to to promote oxidative stress. Different fluorescent probes were employed to monitor iron oxidative status, ROS formation, labile iron pool, glutathione content and cell death. Detoxifying proteins were quantified by Western blot. Upon iron overload, AFG3L2-KO cortical neurons showed a significantly higher percentage of cell death than the WT counterpart. Surprisingly, with culture time, AFG3L2-KO neurons acquired a protective phenotype that made them more resistant than WT neurons to oxidative conditions. Further investigation revealed that the main antioxidant cellular molecule, glutathione, was not involved in this acquired resistance. On the other hand, during their ageing in culture, KO neurons showed an increase in the expression of SOD2 and peroxiredoxin III, two mitochondrial detoxifying proteins that appear to be involved in this compensatory and protective mechanism.

Francesca Maltecca – One of the best experts on this subject based on the ideXlab platform.

  • A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy.
    Acta neuropathologica communications, 2020
    Co-Authors: Valentina Baderna, Joshua Schultz, Lisa S. Kearns, Michael C Fahey, Bryony A. Thompson, Jonathan B Ruddle, Aamira Huq, Francesca Maltecca
    Abstract:

    Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed. Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G > A; p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5). Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA.

  • Upregulation of Peroxiredoxin 3 Protects AFG3L2-KO Cortical Neurons In Vitro from Oxidative Stress: A Paradigm for Neuronal Cell Survival under Neurodegenerative Conditions.
    Oxidative medicine and cellular longevity, 2019
    Co-Authors: Barbara Bettegazzi, Giorgio Casari, Francesca Maltecca, Fabio Grohovaz, Daniele Zacchetti, Ilaria Pelizzoni, Floramarida Salerno Scarzella, Lisa Michelle Restelli, Franca Codazzi
    Abstract:

    Several neurodegenerative disorders exhibit selective vulnerability, with subsets of neurons more affected than others, possibly because of the high expression of an altered gene or the presence of particular features that make them more susceptible to insults. On the other hand, resilient neurons may display the ability to develop antioxidant defenses, particularly in diseases of mitochondrial origin, where oxidative stress might contribute to the neurodegenerative process. In this work, we investigated the oxidative stress response of embryonic fibroblasts and cortical neurons obtained from AFG3L2-KO mice. AFG3L2 encodes a subunit of a protease complex that is expressed in mitochondria and acts as both quality control and regulatory enzyme affecting respiration and mitochondrial dynamics. When cells were subjected to an acute oxidative stress protocol, the survival of AFG3L2-KO MEFs was not significantly influenced and was comparable to that of WT; however, the basal level of the antioxidant molecule glutathione was higher. Indeed, glutathione depletion strongly affected the viability of KO, but not of WT MEF, thereby indicating that oxidative stress is more elevated in KO MEF even though well controlled by glutathione. On the other hand, when cortical KO neurons were put in culture, they immediately appeared more vulnerable than WT to the acute oxidative stress condition, but after few days in vitro, the situation was reversed with KO neurons being more resistant than WT to acute stress. This compensatory, protective competence was not due to the upregulation of glutathione, rather of two mitochondrial antioxidant proteins: superoxide dismutase 2 and, at an even higher level, peroxiredoxin 3. This body of evidence sheds light on the capability of neurons to activate neuroprotective pathways and points the attention to peroxiredoxin 3, an antioxidant enzyme that might be critical for neuronal survival also in other disorders affecting mitochondria.

  • m-AAA and i-AAA complexes coordinate to regulate OMA1, the stress-activated supervisor of mitochondrial dynamics.
    Journal of cell science, 2018
    Co-Authors: Francesco Consolato, Francesca Maltecca, Susanna Tulli, Irene Sambri, Giorgio Casari
    Abstract:

    The proteolytic processing of dynamin like GTPase OPA1, mediated by the activity of both YME1L1 ( i- AAA protease complex) and OMA1, is a crucial step in the regulation of mitochondrial dynamics. OMA1 is a zinc metallopeptidase of the inner mitochondrial membrane that undergoes pre-activating proteolytic and auto-proteolytic cleavage after mitochondrial import. Here, we identify AFG3L2 ( m- AAA complex) as the major protease mediating this event by maturing the pre-pro-OMA1 of 60 kDa to the pro-OMA1 form of 40 kDa by severing the amino-terminal part without recognizing specific consensus sequence. Therefore, m- AAA and i- AAA complexes coordinately regulate OMA1 processing and turnover, and consequently OPA1 isoforms, thus adding new information in the comprehension of the molecular mechanisms in mitochondrial dynamics and of neurodegenerative diseases affected by these phenomena.

Elena I. Rugarli – One of the best experts on this subject based on the ideXlab platform.

  • Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration.
    Glia, 2019
    Co-Authors: Sara Murru, Esther Barth, Thomas Langer, Simon Hess, Eva R. Almajan, Désirée Schatton, Steffen Hermans, Susanne Brodesser, Peter Kloppenburg, Elena I. Rugarli
    Abstract:

    Mitochondrial dysfunction causes neurodegeneration but whether impairment of mitochondrial homeostasis in astrocytes contributes to this pathological process remains largely unknown. The m-AAA protease exerts quality control and regulatory functions crucial for mitochondrial homeostasis. AFG3L2, which encodes one of the subunits of the m-AAA protease, is mutated in spinocerebellar ataxia SCA28 and in infantile syndromes characterized by spastic-ataxia, epilepsy and premature death. Here, we investigate the role of AFG3L2 and its redundant homologue Afg3l1 in the Bergmann glia (BG), radial astrocytes of the cerebellum that have functional connections with Purkinje cells (PC) and regulate glutamate homeostasis. We show that astrocyte-specific deletion of AFG3L2 in the mouse leads to late-onset motor impairment and to degeneration of BG, which display aberrant morphology, altered expression of the glutamate transporter EAAT2, and a reactive inflammatory signature. The neurological and glial phenotypes are drastically exacerbated when astrocytes lack both Afg31l and AFG3L2, and therefore, are totally depleted of the m-AAA protease. Moreover, mitochondrial stress responses and necroptotic markers are induced in the cerebellum. In both mouse models, targeted BG show a fragmented mitochondrial network and loss of mitochondrial cristae, but no signs of respiratory dysfunction. Importantly, astrocyte-specific deficiency of Afg3l1 and AFG3L2 triggers secondary morphological degeneration and electrophysiological changes in PCs, thus demonstrating a non-cell-autonomous role of glia in neurodegeneration. We propose that astrocyte dysfunction amplifies both neuroinflammation and glutamate excitotoxicity in patients carrying mutations in AFG3L2, leading to a vicious circle that contributes to neuronal death.

  • The Mitochondrial m-AAA Protease Prevents Demyelination and Hair Greying
    PLoS Genetics, 2016
    Co-Authors: Shuaiyu Wang, Julie Jacquemyn, Sara Murru, Paola Martinelli, Esther Barth, Thomas Langer, Carien M. Niessen, Elena I. Rugarli
    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.

  • AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival
    The Journal of clinical investigation, 2012
    Co-Authors: Eva-ruxandra Almajan, Paola Martinelli, Esther Barth, Thomas Langer, Peter Kloppenburg, Ricarda Richter, Lars Paeger, Thorsten Decker, Nils-göran Larsson, Elena I. Rugarli
    Abstract:

    Mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia type 28 and spastic ataxia-neuropathy syndrome in humans; however, the pathogenic mechanism is still unclear. AFG3L2 encodes a subunit of the mitochondrial m-AAA protease, previously implicated in quality control of misfolded inner mitochondrial membrane proteins and in regulatory functions via processing of specific substrates. Here, we used a conditional AFG3L2 mouse model that allows restricted deletion of the gene in Purkinje cells (PCs) to shed light on the pathogenic cascade in the neurons mainly affected in the human diseases. We demonstrate a cell-autonomous requirement of AFG3L2 for survival of PCs. Examination of PCs prior to neurodegeneration revealed fragmentation and altered distribution of mitochondria in the dendritic tree, indicating that abnormal mitochondrial dynamics is an early event in the pathogenic process. Moreover, PCs displayed features pointing to defects in mitochondrially encoded respiratory chain subunits at early stages. To unravel the underlying mechanism, we examined a constitutive knockout of AFG3L2, which revealed a decreased rate of mitochondrial protprotein synthesis associated with impaired mitochondrial ribosome assembly. We therefore propose that defective mitochondrial protprotein synthesis, leading to early-onset fragmentation of the mitochondrial network, is a central causative factor in AFG3L2-related neurodegeneration.

Paola Martinelli – One of the best experts on this subject based on the ideXlab platform.

  • The Mitochondrial m-AAA Protease Prevents Demyelination and Hair Greying
    PLoS Genetics, 2016
    Co-Authors: Shuaiyu Wang, Julie Jacquemyn, Sara Murru, Paola Martinelli, Esther Barth, Thomas Langer, Carien M. Niessen, Elena I. Rugarli
    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.

  • loss of the m aaa protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation
    The EMBO Journal, 2014
    Co-Authors: Arun Kumar Kondadi, Shuaiyu Wang, Paola Martinelli, Sara Montagner, Nikolay Kladt, Anne Korwitz, David Herholz, Michael J. Baker, Astrid C. Schauss, Thomas Langer
    Abstract:

    The m-AAA protease subunit AFG3L2 is involved in degradation and processing of substrates in the inner mitochondrial membrane. Mutations in AFG3L2 are associated with spinocerebellar ataxia SCA28 in humans and impair axonal development and neuronal survival in mice. The loss of AFG3L2 causes fragmentation of the mitochondrial network. However, the pathogenic mechanism of neurodegeneration in the absence of AFG3L2 is still unclear. Here, we show that depletion of AFG3L2 leads to a specific defect of anterograde transport of mitochondria in murine cortical neurons. We observe similar transport deficiencies upon loss of AFG3L2 in OMA1-deficient neurons, indicating that they are not caused by OMA1-mediated degradation of the dynamin-like GTPase OPA1 and inhibition of mitochondrial fusion. Treatment of neurons with antioxidants, such as N-acetylcysteine or vitamin E, or decreasing tau levels in axons restored mitochondrial transport in AFG3L2-depleted neurons. Consistently, tau hyperphosphorylation and activation of ERK kinases are detected in mouse neurons postnatally deleted for AFG3L2. We propose that reactive oxygen species signaling leads to cytoskeletal modifications that impair mitochondrial transport in neurons lacking AFG3L2.

  • Loss of the m‐AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation
    The EMBO journal, 2014
    Co-Authors: Arun Kumar Kondadi, Shuaiyu Wang, Paola Martinelli, Sara Montagner, Nikolay Kladt, Anne Korwitz, David Herholz, Michael J. Baker, Astrid C. Schauss, Thomas Langer
    Abstract:

    The m-AAA protease subunit AFG3L2 is involved in degradation and processing of substrates in the inner mitochondrial membrane. Mutations in AFG3L2 are associated with spinocerebellar ataxia SCA28 in humans and impair axonal development and neuronal survival in mice. The loss of AFG3L2 causes fragmentation of the mitochondrial network. However, the pathogenic mechanism of neurodegeneration in the absence of AFG3L2 is still unclear. Here, we show that depletion of AFG3L2 leads to a specific defect of anterograde transport of mitochondria in murine cortical neurons. We observe similar transport deficiencies upon loss of AFG3L2 in OMA1-deficient neurons, indicating that they are not caused by OMA1-mediated degradation of the dynamin-like GTPase OPA1 and inhibition of mitochondrial fusion. Treatment of neurons with antioxidants, such as N-acetylcysteine or vitamin E, or decreasing tau levels in axons restored mitochondrial transport in AFG3L2-depleted neurons. Consistently, tau hyperphosphorylation and activation of ERK kinases are detected in mouse neurons postnatally deleted for AFG3L2. We propose that reactive oxygen species signaling leads to cytoskeletal modifications that impair mitochondrial transport in neurons lacking AFG3L2.