A Mutation in the Inner Mitochondrial Membrane Peptidase 2-Like Gene (Immp2l) Affects Mitochondrial Function and Impairs Fertility in Mice1

Lü, Biao; Poirier, Christophe; Gáspár, Tamás; Gratzke, Christian; Harrison, Wilbur R.; Busija, David W.; Matzuk, Martin M.; Andersson, Karl‐Erik; Overbeek, Paul A.; Bishop, Colin E.

doi:10.1095/biolreprod.107.065987

Cited by 105 publications

(193 citation statements)

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“…Our observation of increased protein nitration in old mutant mice is consistent with our previous observation of excessive superoxide generation from mitochondria of mutant mice (Lu et al ., 2008). Physiological levels of nitric oxide are necessary for the survival of differentiated cerebellar granule cells (Ciani et al ., 2002).…”

Section: Resultsmentioning

confidence: 99%

“…nNOS is highly expressed in cerebellar granule neurons (Bredt et al ., 1990; Bredt & Snyder, 1992). We previously reported that −/− mice show erectile dysfunction and decreased hypothalamic cGMP level (Lu et al ., 2008; Han et al ., 2013), both could result from negation of nitric oxide by mitochondrial superoxide. Quantitative RT–PCR revealed that nNOS and iNOS expression were increased in cerebella of young mutant mice, whereas eNOS expression was not significantly different between +/+ and −/− mice regardless of age (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We used immunohistochemistry to compare the expression of VDAC1, a mitochondrial protein widely used as a loading control for mitochondrial proteins. This voltage‐dependent anion channel, a mitochondrial outer membrane protein, is highly unlikely to be affected by IMMP2L deficiency in the mutants, because IMMP2L's substrates are inner membrane proteins, and so far only CYC1 and GPD2 are known IMMP2L substrates (Lu et al ., 2008). Similar to SOD2, we found specific reduction of DVAC1 expression in granule neurons of old mutant mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It cleaves the space‐sorting signal peptide sequences of cytochrome c1 (CYC1) and mitochondrial glycerol phosphate dehydrogenase 2 (GPD2), the two known substrates for IMMP2L. We reported that mutation of both Immp2l alleles impaired processing of CYC1 and GPD2 signal peptide sequences in mice (Lu et al ., 2008). Isolated mitochondrial from Immp2l −/− mice produced superoxide at an increased rate (Lu et al ., 2008), but showed normal GPD2 and mitochondrial complex III activities (CYC1 is a subunit of complex III) and mitochondrial bioenergetic capacity (Bharadwaj et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Although their lifespans are not reduced compared to normal control mice, Immp2l −/− mice show erectile dysfunction, defective oogenesis (Lu et al ., 2008), reduced food intake (Han et al ., 2013), bladder dysfunction (Soler et al ., 2010), early onset of ataxia and kyphosis (George et al ., 2011), and age‐dependent spermatogenic damage (Lu et al ., 2008; George et al ., 2012). We propose that these abnormal phenotypes in Immp2l −/− mice could result from two major effects of elevated mitochondrial superoxide production: negation of the signaling molecule nitric oxide (NO), and increased formation of other forms of reactive oxygen species.…”

Section: Introductionmentioning

confidence: 99%

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The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Liu

Lü

2015

Aging Cell

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SummaryReactive oxygen species are implicated in age‐associated neurodegeneration, although direct in vivo evidence is lacking. We recently showed that mice with a mutation in the Inner Mitochondrial Membrane Peptidase 2‐like (Immp2l) gene had elevated levels of mitochondrial superoxide, impaired fertility and age‐associated phenotypes, including kyphosis and ataxia. Here we show that ataxia and cerebellar hypoplasia occur in old mutant mice (> 16 months). Cerebellar granule neurons (CGNs) are significantly underrepresented; Purkinje cells and cells in the molecular layer are not affected. Treating mutant mice with the mitochondria‐targeted antioxidant SkQ1 from 6 weeks to 21 months protected cerebellar granule neurons. Apoptotic granule neurons were observed in mutant mice but not in age‐matched normal control mice or SkQ1‐treated mice. Old mutant mice showed increased serum protein carbonyl content, cerebellar 4‐hydroxynonenal (HNE), and nitrotyrosine modification compared to old normal control mice. SOD2 expression was increased in Purkinje cells but decreased in granule neurons of old mutant mice. Mitochondrial marker protein VDAC1 also was decreased in CGNs of old mutant mice, suggesting decreased mitochondrial number. SkQ1 treatment decreased HNE and nitrotyrosine modification, and restored SOD2 and VDAC1 expression in CGNs of old mutant mice. Neuronal expression of nitric oxide synthase was increased in cerebella of young mutant mice but decreased in old mutant mice. Our work provides evidence for a causal role of oxidative stress in neurodegeneration of Immp2l mutant mice. The Immp2l mutant mouse model could be valuable in elucidating the role of oxidative stress in age‐associated neurodegeneration.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Liu

Lü

2015

Aging Cell

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Mitochondrial proteases in human diseases

Gala

Vögtle

2021

FEBS Letters

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Mitochondria contain more than 1000 different proteins, including several proteolytic enzymes. These mitochondrial proteases form a complex system that performs limited and terminal proteolysis to build the mitochondrial proteome, maintain and control its functions or degrade mitochondrial proteins and peptides. During protein biogenesis presequence proteases cleave and degrade mitochondrial targeting signals to obtain mature functional proteins. Processing by proteases also exerts a regulatory role in modulation of mitochondrial functions and quality control enzymes degrade misfolded, aged or superfluous proteins. Depending on their different functions and substrates, defects in mitochondrial proteases can affect the majority of the mitochondrial proteome or only a single protein. Consequently, mutations in mitochondrial proteases have been linked to several human diseases. This review gives an overview of the components and functions of the mitochondrial proteolytic machinery and highlights the pathological consequences of dysfunctional mitochondrial protein processing and turnover.

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Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

Busija

Rutkai

Dutta

et al. 2016

Comprehensive Physiology

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Mitochondria not only produce energy in the form of ATP to support the activities of cells comprising the neurovascular unit, but mitochondrial events, such as depolarization and/or ROS release, also initiate signaling events which protect the endothelium and neurons against lethal stresses via pre-/postconditioning as well as promote changes in cerebral vascular tone. Mitochondrial depolarization in vascular smooth muscle (VSM), via pharmacological activation of the ATP-dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels), leads to vasorelaxation through generation of calcium sparks by the sarcoplasmic reticulum and subsequent downstream signaling mechanisms. Increased release of ROS by mitochondria has similar effects. Relaxation of VSM can also be indirectly achieved via actions of nitric oxide (NO) and other vasoactive agents produced by endothelium, perivascular and parenchymal nerves, and astroglia following mitochondrial activation. Additionally, NO production following mitochondrial activation is involved in neuronal preconditioning. Cerebral arteries from female rats have greater mitochondrial mass and respiration and enhanced cerebral arterial dilation to mitochondrial activators. Preexisting chronic conditions such as insulin resistance and/or diabetes impair mitoKATP channel relaxation of cerebral arteries and preconditioning. Surprisingly, mitoKATP channel function after transient ischemia appears to be retained in the endothelium of large cerebral arteries despite generalized cerebral vascular dysfunction. Thus, mitochondrial mechanisms may represent the elusive signaling link between metabolic rate and blood flow as well as mediators of vascular change according to physiological status. Mitochondrial mechanisms are an important, but underutilized target for improving vascular function and decreasing brain injury in stroke patients. © 2016 American Physiological Society. Compr Physiol 6:1529-1548, 2016.

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A Mutation in the Inner Mitochondrial Membrane Peptidase 2-Like Gene (Immp2l) Affects Mitochondrial Function and Impairs Fertility in Mice1

Cited by 105 publications

References 47 publications

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Mitochondrial proteases in human diseases

Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

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