Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice

Sun, Kaihua; Johnson, Bruce M.; Gunn, Teresa M.

doi:10.1016/j.neurobiolaging.2007.07.012

Cited by 36 publications

(48 citation statements)

References 45 publications

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“…Independently of whether mitochondrial dysfunction is a cause or consequence of neurodegeneration (Sun et al, 2007;Bogaerts et al, 2008), our results suggest that inflammation-induced i-mtNOS is probably related to mitochondrial failure in the MPTP model of PD (Przedborski et al, 2004). In fact, MPTP reduced complex I activity by 48% and 29% in SN and ST, respectively, and this different degree of inhibition agrees well with the different i-mtNOS activity and oxidative/ nitrosative stress observed in SN and ST mitochondria of mice treated with MPTP.…”

Section: Discussionsupporting

confidence: 82%

Melatonin and its brain metabolite N¹‐acetyl‐5‐methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice

Tapias

Escames

López

et al. 2009

J of Neuroscience Research

106

108

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Melatonin prevents mitochondrial failure in models of sepsis through its ability to inhibit the expression and activity of both cytosolic (iNOS) and mitochondrial (i-mtNOS) inducible nitric oxide synthases. Because Parkinson's disease (PD), like sepsis, is associated with iNOS induction, we assessed the existence of changes in iNOS/i-mtNOS and their relation with mitochondrial dysfunction in the MPTP model of PD, which also displays increased iNOS expression. We also evaluated the role of melatonin (aMT) and its brain metabolite, N(1)-acetyl-5-methoxykynuramine (AMK), in preventing i-mtNOS induction and mitochondrial failure in this model of PD. Mitochondria from substantia nigra (SN) and, to a lesser extent, from striatum (ST) showed a significant increase in i-mtNOS activity, nitrite levels, oxidative stress, and complex I inhibition after MPTP treatment. MPTP-induced i-mtNOS was probably related to mitochondrial failure, because its prevention by aMT and AMK reduced oxidative/nitrosative stress and restored complex I activity. These findings represent the first experimental evidence of a potential role for i-mtNOS in the mitochondrial failure of PD and support a novel mechanism in the neuroprotective effects of aMT and AMK.

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Section: Discussionsupporting

confidence: 82%

Melatonin and its brain metabolite N¹‐acetyl‐5‐methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice

Tapias

Escames

López

et al. 2009

J of Neuroscience Research

106

108

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“…TAL (also known as LRSAM1) and MDM2 are two different E3 ubiquitin ligases, which are involved in the ubiquitinylation of TSG101 protein [38][39][40]. MGRN1 null mutants exhibit problems in pigmenttype switching, induce oxidative stress, and show mitochondrial dysfunction preceding neurodegeneration [41,42].…”

Section: Molecular Functions Of Mgrn1 In Neurodegenerative Diseasesmentioning

confidence: 99%

Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

et al. 2015

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In healthy cell, inappropriate accumulation of poor or damaged proteins is prevented by cellular quality control system. Autophagy and ubiquitin proteasome system (UPS) provides regular cytoprotection against proteotoxicity induced by abnormal or disruptive proteins. E3 ubiquitin ligases are crucial components in this defense mechanism. Mahogunin Ring Finger-1 (MGRN1), an E3 ubiquitin ligase of the Really Interesting New Gene (RING) finger family, plays a pivotal role in many biological and cellular mechanisms. Previous findings indicate that lack of functions of MGRN1 can cause spongiform neurodegeneration, congenital heart defects, abnormal left-right patterning, and mitochondrial dysfunctions in mice brains. However, the detailed molecular pathomechanism of MGRN1 in cellular functions and diseases is not well known. This article comprehensively represents the molecular nature, characterization, and functions of MGRN1; we also summarize possible beneficiary aspects of this novel E3 ubiquitin ligase. Here, we review recent literature on the role of MGRN1 in the neuro-pathobiological mechanisms, with precise focus on the processes of neurodegeneration, and thereby propose new lines of potential targets for therapeutic intervention.

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“…Although recent studies have suggested that MGRN1 has a role in oxidative stress (Sun et al, 2007;Chhangani and Mishra, 2013), the molecular basis for these observations was elusive.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin mediated regulation of the E3 ligase GP78 by Mahogunin in trans affects mitochondrial homeostasis

Mukherjee

Chakrabarti

2016

Journal of Cell Science

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Cellular quality control provides an efficient surveillance system to regulate mitochondrial turnover. This study elucidates a new interaction between the cytosolic E3 ligase mahogunin RING finger 1 (MGRN1) and the endoplasmic reticulum (ER) ubiquitin E3 ligase GP78 (also known as AMFR). Loss of Mgrn1 function has been implicated in late-onset spongiform neurodegeneration and congenital heart defects, among several developmental defects. Here, we show that MGRN1 ubiquitylates GP78 in trans through noncanonical K11 linkages. This helps maintain constitutively low levels of GP78 in healthy cells, in turn downregulating mitophagy. GP78, however, does not regulate MGRN1. When mitochondria are stressed, cytosolic Ca 2+ increases. This leads to a reduced interaction between MGRN1 and GP78 and its compromised ubiquitylation. Chelating Ca 2+ restores association between the two ligases and the in trans ubiquitylation. Catalytic inactivation of MGRN1 results in elevated levels of GP78 and a consequential increase in the initiation of mitophagy. This is important because functional depletion of MGRN1 by the membrane-associated disease-causing prion protein Ctm PrP affects polyubiquitylation and degradation of GP78, also leading to an increase in mitophagy events. This suggests that MGRN1 participates in mitochondrial quality control and could contribute to neurodegeneration in a subset of Ctm PrP-mediated prion diseases.

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Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice

Cited by 36 publications

References 45 publications

Melatonin and its brain metabolite N¹‐acetyl‐5‐methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice

Melatonin and its brain metabolite N¹‐acetyl‐5‐methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice

Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

Ubiquitin mediated regulation of the E3 ligase GP78 by Mahogunin in trans affects mitochondrial homeostasis

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Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice

Cited by 36 publications

References 45 publications

Melatonin and its brain metabolite N1‐acetyl‐5‐methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice

Melatonin and its brain metabolite N1‐acetyl‐5‐methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice

Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

Ubiquitin mediated regulation of the E3 ligase GP78 by Mahogunin in trans affects mitochondrial homeostasis

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Melatonin and its brain metabolite N¹‐acetyl‐5‐methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice

Melatonin and its brain metabolite N¹‐acetyl‐5‐methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice