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Review
. 2012 Mar 21;31(6):1336-49.
doi: 10.1038/emboj.2012.38. Epub 2012 Feb 21.

Mitochondrial quality control: a matter of life and death for neurons

Elena I Rugarli  1 , Thomas Langer
Affiliations
Review

Mitochondrial quality control: a matter of life and death for neurons

Elena I Rugarli et al. EMBO J. .

Abstract

Neuronal survival critically depends on the integrity and functionality of mitochondria. A hierarchical system of cellular surveillance mechanisms protects mitochondria against stress, monitors mitochondrial damage and ensures the selective removal of dysfunctional mitochondrial proteins or organelles. Mitochondrial proteases emerge as central regulators that coordinate different quality control (QC) pathways within an interconnected network of mechanisms. A failure of this system causes neuronal loss in a steadily increasing number of neurodegenerative disorders, which include Parkinson's disease, spinocerebellar ataxia, spastic paraplegia and peripheral neuropathies. Here, we will discuss the role of the mitochondrial QC network for neuronal survival and neurodegeneration.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
(A) The hierarchical network of mitochondrial QC mechanisms. Intramitochondrial proteases and molecular chaperone proteins maintain mitochondrial proteostasis. Stress conditions induce a transcriptional programme (mitochondrial unfolded protein response, mtUPR) that increases protein levels of chaperones and proteases in mitochondria. Fusion allowing content mixing contributes to mitochondrial integrity and stress-induced mitochondrial hyperfusion may alleviate mild mitochondrial stress. A dysfunction of mitochondria inhibits fusion and triggers fragmentation of the mitochondrial network, which is associated with mitophagy or, under conditions of severe damage, leads to mitochondrial outer membrane permeabilization and apoptosis. (B) Submitochondrial localization of proteases with functions in mitochondrial QC. i-AAA, i-AAA protease; m-AAA, m-AAA protease; OM, outer membrane; IMS, intermembrane space; IM, inner membrane.
Figure 2
Figure 2
Possible pathogenic mechanisms of neurodegenerative disorders caused by mutations in m-AAA protease subunits. Mutations in the m-AAA protease subunit AFG3L2 impair the activity of both homo- and hetero-oligomeric m-AAA isoenzymes, while mutations in paraplegin (SPG7) affect only the hetero-oligomeric m-AAA protease. Accumulating misfolded polypeptides or deficiencies in mitochondrial biogenesis and dynamics may interfere with mitochondrial energy output and axonal trafficking of mitochondria.
Figure 3
Figure 3
Mitochondrial proteases regulate mitochondrial morphology and turnover. (A) Constitutive and stress-induced OPA1 cleavage. Newly synthesized OPA1 precursor molecules are matured and converted into L-OPA1 upon import into mitochondria, likely by the mitochondrial processing peptidase. A fraction of L-OPA1 molecules is subsequently cleaved at position S2 by YME1L and likely at position S1 by OMA1. Under stress conditions (e.g., low ΔΨm, low matrix ATP), OMA1 degrades L-OPA1 molecules completely into S-OPA1. (B) Accumulation of PINK1 at mitochondrial surface. PINK1 precursor proteins are imported into mitochondria in ΔΨm-dependent manner, accompanied by maturation, likely by the mitochondrial processing peptidase. Newly imported PINK1 is degraded in the inner membrane by PARL and an MG132-sensitive, yet to be identified peptidase. A dysfunction of mitochondria (low ΔΨm) impairs import but not mitochondrial targeting of PINK1 resulting in its accumulation at the mitochondrial surface. OM, outer membrane; IMS, intermembrane space; IM, inner membrane.
Figure 4
Figure 4
Mitochondrial dysfunction triggers a fatal cascade leading to axonal damage and apoptosis. Low ΔΨm induce the degradation of dynamin-like GTPases in the inner and outer membrane, proteolytic remodelling of the mitochondrial proteome in the outer membrane and the turnover of Miro inhibiting fusion and axonal transport of mitochondria. Mitophagy of damaged mitochondrial fragments may protect against neurodegeneration, but severe damage impairs axonal trafficking of mitochondria and Ca2+ homeostasis, ultimately leading to axonal swelling and apoptosis. IM, inner membrane; OM, outer membrane; MFNs, mitofusins.
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References

    1. Akepati VR, Muller EC, Otto A, Strauss HM, Portwich M, Alexander C (2008) Characterization of OPA1 isoforms isolated from mouse tissues. J Neurochem 106: 372–383 - PubMed
    1. Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS, Wissinger B (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26: 211–215 - PubMed
    1. Alikhani N, Guo L, Yan S, Du H, Pinho CM, Chen JX, Glaser E, Yan SS (2011) Decreased proteolytic activity of the mitochondrial amyloid-beta degrading enzyme, prep peptidasome, in Alzheimer's disease brain mitochondria. J Alzheimers Dis 27: 75–87 - PMC - PubMed
    1. Arnold B, Cassady SJ, VanLaar VS, Berman SB (2011) Integrating multiple aspects of mitochondrial dynamics in neurons: age-related differences and dynamic changes in a chronic rotenone model. Neurobiol Dis 41: 189–200 - PMC - PubMed
    1. Baker MJ, Tatsuta T, Langer T (2011) Quality control of mitochondrial proteostasis. Cold Spring Harb Perspect Biol 3: pii: a007559 - PMC - PubMed

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