IMMP2L: a mitochondrial protease suppressing cellular senescence

Sica, Valentina; Kroemer, Guido

doi:10.1038/s41422-018-0051-5

Cited by 5 publications

(3 citation statements)

References 13 publications

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“…Normally, IMMP2L processes and thus activates the mitochondrial metabolic enzyme glycerol‐3‐phosphate dehydrogenase (GPD2) and the cell death regulator apoptosis‐inducing factor (AIF). Impediment of such IMMP2L‐dependent proteolysis drives senescence by reprogramming the redox status of mitochondria, phospholipid metabolism, and associated signaling and by preventing cell death (Sica & Kroemer, 2018 ; Yuan et al, 2018 ).…”

Section: Contribution Of Proteases To the Hallmarks Of Agingmentioning

confidence: 99%

Contribution of proteases to the hallmarks of aging and to age‐related neurodegeneration

et al. 2022

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Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age‐associated diseases. The ubiquitin–proteasome and autophagy‐lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Here, we examine the role of proteases in aging and age‐related neurodegeneration. Proteases are present across cell compartments, including the extracellular space, and their substrates encompass cellular constituents, proteins with signaling functions, and misfolded proteins. Proteolytic processing by proteases can lead to changes in the activity and localization of substrates or to their degradation. Proteases cooperate with the autophagy‐lysosome and ubiquitin–proteasome systems but also have independent proteolytic roles that impact all hallmarks of cellular aging. Specifically, proteases regulate mitochondrial function, DNA damage repair, cellular senescence, nutrient sensing, stem cell properties and regeneration, protein quality control and stress responses, and intercellular signaling. The capacity of proteases to regulate cellular functions translates into important roles in preserving tissue homeostasis during aging. Consequently, proteases influence the onset and progression of age‐related pathologies and are important determinants of health span. Specifically, we examine how certain proteases promote the progression of Alzheimer's, Huntington's, and/or Parkinson's disease whereas other proteases protect from neurodegeneration. Mechanistically, cleavage by proteases can lead to the degradation of a pathogenic protein and hence impede disease pathogenesis. Alternatively, proteases can generate substrate byproducts with increased toxicity, which promote disease progression. Altogether, these studies indicate the importance of proteases in aging and age‐related neurodegeneration.

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Section: Contribution Of Proteases To the Hallmarks Of Agingmentioning

confidence: 99%

Contribution of proteases to the hallmarks of aging and to age‐related neurodegeneration

et al. 2022

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“…The current understanding of mechanisms underlying structural and functional changes of the components of the cardiovascular (CV) system, including large- and medium-sized arteries, the heart, and the kidneys, is that they are the result of metabolic, oxidative, and hemodynamic stress, as an effect of a long-term action on cells and tissues of this system, of overlapping CV risk factors, such as hypertension, obesity, and T2D, synergized with the effects of stochastic and senescent processes [ 23 , 24 ]. Some particular mechanisms, which, by acting simultaneously, may lead to dysfunction of the microvasculature and development of increased stiffness of large arteries, include decreased availability of the vasodilator substance nitrite oxide, hyperproduction of ROS due to mitochondrial dysfunction, macromolecule modification by glycation and oxidation, activation of the renin-angiotensin system (RAS), increased activity of the tissue type angiotensin II (ANG II), residential cell switching on the senescence-associated secretory phenotype, loss of autophagy (a mechanism of cell waste management), and impairment of protein homeostasis (proteostasis) [ 24 , 25 , 26 , 27 ].…”

Section: Chronic Inflammation Associated With Target Organ Damage In ...mentioning

confidence: 99%

Cross-Talk between the Cytokine IL-37 and Thyroid Hormones in Modulating Chronic Inflammation Associated with Target Organ Damage in Age-Related Metabolic and Vascular Conditions

Bosnić

Majnarić

Wittlinger

2022

IJMS

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Chronic inflammation is considered to be the main mechanism contributing to the development of age-related metabolic and vascular conditions. The phases of chronic inflammation that mediate the progression of target organ damage in these conditions are poorly known, however. In particular, there is a paucity of data on the link between chronic inflammation and metabolic disorders. Based on some of our own results and recent developments in our understanding of age-related inflammation as a whole-body response, we discuss the hypothesis that cross-talk between the cytokine IL-37 and thyroid hormones could be the key regulatory mechanism that justifies the metabolic effects of chronic tissue-related inflammation. The cytokine IL-37 is emerging as a strong natural suppressor of the chronic innate immune response. The effect of this cytokine has been identified in reversing metabolic costs of chronic inflammation. Thyroid hormones are known to regulate energy metabolism. There is a close link between thyroid function and inflammation in elderly individuals. Nonlinear associations between IL-37 and thyroid hormones, considered within the wider clinical context, can improve our understanding of the phases of chronic inflammation that are associated with target organ damage in age-related metabolic and vascular conditions.

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“…Together, GPD1 and GPD2 constitute the glycerol phosphate shuttle, which generates FADH 2 for the mitochondrial ETC and NAD+ for glycolysis in the cytosol. The coordinated action of GPD1 and GPD2 results in the transfer of two reducing equivalents from G3P to the mobile electron carrier ubiquinone (Coenzyme Q10) which in turn passes these electrons to CYC1 located downstream in the ETC (80,81,(178)(179)(180).…”

Section: Optimisation Of Mitochondrial Supplymentioning

confidence: 99%

Tourette Syndrome Risk Genes Regulate Mitochondrial Dynamics, Structure, and Function

2021

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Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and vocal tics with an estimated prevalence of 1% in children and adolescents. GTS has high rates of inheritance with many rare mutations identified. Apart from the role of the neurexin trans-synaptic connexus (NTSC) little has been confirmed regarding the molecular basis of GTS. The NTSC pathway regulates neuronal circuitry development, synaptic connectivity and neurotransmission. In this study we integrate GTS mutations into mitochondrial pathways that also regulate neuronal circuitry development, synaptic connectivity and neurotransmission. Many deleterious mutations in GTS occur in genes with complementary and consecutive roles in mitochondrial dynamics, structure and function (MDSF) pathways. These genes include those involved in mitochondrial transport (NDE1, DISC1, OPA1), mitochondrial fusion (OPA1), fission (ADCY2, DGKB, AMPK/PKA, RCAN1, PKC), mitochondrial metabolic and bio-energetic optimization (IMMP2L, MPV17, MRPL3, MRPL44). This study is the first to develop and describe an integrated mitochondrial pathway in the pathogenesis of GTS. The evidence from this study and our earlier modeling of GTS molecular pathways provides compounding support for a GTS deficit in mitochondrial supply affecting neurotransmission.

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IMMP2L: a mitochondrial protease suppressing cellular senescence

Cited by 5 publications

References 13 publications

Contribution of proteases to the hallmarks of aging and to age‐related neurodegeneration

Contribution of proteases to the hallmarks of aging and to age‐related neurodegeneration

Cross-Talk between the Cytokine IL-37 and Thyroid Hormones in Modulating Chronic Inflammation Associated with Target Organ Damage in Age-Related Metabolic and Vascular Conditions

Tourette Syndrome Risk Genes Regulate Mitochondrial Dynamics, Structure, and Function

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