PINK1 alleviates palmitate induced insulin resistance in HepG2 cells by suppressing ROS mediated MAPK pathways

Cang, Xiaomin; Wang, Xiaohua; Liu, Pingli; Wu, Xianwei; Chen, Jinfeng; Wu, Gang; Jin, Yan; Xu, Feng; Su, Jianbin; Wan, Chunhua; Wang, Xueqin

doi:10.1016/j.bbrc.2016.07.004

Cited by 35 publications

(24 citation statements)

References 17 publications

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“…This marked effect is not unexpected, since PINK1 (short for PTEN induced kinase 1) is downstream of PTEN, a phosphatase that antagonizes the kinase PI3K, which is an upstream modulator of the MAPK phosphorylation cascade at various levels. Furthermore, the interaction of PINK1 with the MAPK pathway has already been demonstrated experimentally in neuroblastoma cells, astrocytes, HeLa, and HepG2 liver cells [ 51 , 64 – 66 ].…”

Section: Resultsmentioning

confidence: 99%

Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation

Torres-Odio¹,

Key²,

Hoepken³

et al. 2017

J Neuroinflammation

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BackgroundPINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types.MethodsGlobal transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts.ResultsIn a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”. Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3, and Nfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance. Immunohistochemistry showed pronounced cellular response of Iba1-positive microglia and GFAP-positive astrocytes; brain lipidomics observed increases of ceramides as neuroinflammatory signs at old age.In a second approach, we assessed PINK1 deficiency in the presence of a stressor. Marked dysregulations of microbial defense factors Ifit3 and Rsad2 were consistently observed upon five analyses: (1) Pink1 −/− primary neurons in the first weeks after brain dissociation, (2) aged Pink1 −/− midbrain with transgenic A53T-alpha-synuclein overexpression, (3) human neuroblastoma cells with PINK1-knockdown and murine Pink1 −/− embryonal fibroblasts undergoing acute starvation, (4) triggering mitophagy in these cells with trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP), and (5) subjecting them to pathogenic RNA-analogue poly(I:C). The stress regulation of MAVS, RSAD2, DDX58, IFIT3, IFIT1, and LRRK2 was PINK1 dependent. Dysregulation of some innate immunity genes was also found in skin fibroblast cells from PARK6 patients.ConclusionsThus, an individual biomarker with expression correlating to progression was not identified. Instead, more advanced disease stages involved additional pathways. Hence, our results identify PINK1 deficiency as an early modulator of innate immunity in neurons, which precedes late stages of neuroinflammation during alpha-synuclein spreading.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0928-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation

Torres-Odio¹,

Key²,

Hoepken³

et al. 2017

J Neuroinflammation

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“…During type 2 diabetes, fusion and fission processes are continuously altered in β-cells, and it has been demonstrated that hyperglycemia and enhanced levels of palmitate decrease fusion and inhibit mitochondrial oxygen consumption [54] , [55] . Furthermore, one recent study has demonstrated that PINK1 alleviates palmitate-induced insulin resistance in hepatic cells by suppressing ROS-mediated MAPK pathways [56] .…”

Section: Type 2 Diabetes and Mitochondrial Dynamicsmentioning

confidence: 99%

Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications

Rovira‐Llopis¹,

Bañuls²,

et al. 2017

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Mitochondria play a key role in maintaining cellular metabolic homeostasis. These organelles have a high plasticity and are involved in dynamic processes such as mitochondrial fusion and fission, mitophagy and mitochondrial biogenesis. Type 2 diabetes is characterised by mitochondrial dysfunction, high production of reactive oxygen species (ROS) and low levels of ATP. Mitochondrial fusion is modulated by different proteins, including mitofusin-1 (MFN1), mitofusin-2 (MFN2) and optic atrophy (OPA-1), while fission is controlled by mitochondrial fission 1 (FIS1), dynamin-related protein 1 (DRP1) and mitochondrial fission factor (MFF). PARKIN and (PTEN)-induced putative kinase 1 (PINK1) participate in the process of mitophagy, for which mitochondrial fission is necessary. In this review, we discuss the molecular pathways of mitochondrial dynamics, their impairment under type 2 diabetes, and pharmaceutical approaches for targeting mitochondrial dynamics, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110 and 15-oxospiramilactone. Furthermore, we discuss the pathophysiological implications of impaired mitochondrial dynamics, especially in type 2 diabetes.

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“…PINK1 is generally associated with neuroprotection since loss of function causes PD, but because PINK1 is normally highly turned over at the mitochondrial outer membrane and therefore overexpression and/or altered expression might also induce unwanted downstream events. In one study, PINK1 overexpression restrained MAPK and ROS signaling and mitigated insulin resistance in cell models ( 310 ). Conversely, PINK1 loss corrupts function of islet and β-cells causing impaired glucose uptake and increased levels of plasma insulin ( 311 ).…”

Section: Metformin: Mechanism Of Action In Neurodegenerative Diseasesmentioning

confidence: 99%

The Therapeutic Potential of Metformin in Neurodegenerative Diseases

2018

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The search for treatments for neurodegenerative diseases is a major concern in light of today's aging population and an increasing burden on individuals, families, and society. Although great advances have been made in the last decades to understand the underlying genetic and biological cause of these diseases, only some symptomatic treatments are available. Metformin has long since been used to treat Type 2 Diabetes and has been shown to be beneficial in several other conditions. Metformin is well-tested in vitro and in vivo and an approved compound that targets diverse pathways including mitochondrial energy production and insulin signaling. There is growing evidence for the benefits of metformin to counteract age-related diseases such as cancer, cardiovascular disease, and neurodegenerative diseases. We will discuss evidence showing that certain neurodegenerative diseases and diabetes are explicitly linked and that metformin along with other diabetes drugs can reduce neurological symptoms in some patients and reduce disease phenotypes in animal and cell models. An interesting therapeutic factor might be how metformin is able to balance survival and death signaling in cells through pathways that are commonly associated with neurodegenerative diseases. In healthy neurons, these overarching signals keep energy metabolism, oxidative stress, and proteostasis in check, avoiding the dysfunction and neuronal death that defines neurodegenerative disease. We will discuss the biological mechanisms involved and the relevance of neuronal vulnerability and potential difficulties for future trials and development of therapies.

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PINK1 alleviates palmitate induced insulin resistance in HepG2 cells by suppressing ROS mediated MAPK pathways

Cited by 35 publications

References 17 publications

Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation

Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation

Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications

The Therapeutic Potential of Metformin in Neurodegenerative Diseases

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