Cardiac-specific ablation of the E3 ubiquitin ligase Mdm2 leads to oxidative stress, broad mitochondrial deficiency and early death

Hauck, Ludger; Stanley-Hasnain, Shanna; Fung, Amelia; Grothe, Daniela; Rao, Vivek; Mak, Tak W.; Billia, Filio

doi:10.1371/journal.pone.0189861

Cited by 36 publications

(32 citation statements)

References 161 publications

(176 reference statements)

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“…Several studies have recently shown that MDM2 is associated with rheumatoid arthritis (RA), an autoimmune disorder that causes chronic inflammation and injury of the joints and other organs in the body and the major findings are summarized in Figure . For instance, Assmann et al have examined the roles of two functional single nucleotide polymorphisms (SNPs), MDM2 SNP309 and p53 P72R, in patients who fulfill the American College of Rheumatology criteria for RA.…”

Section: Roles Of Mdm2 In Inflammation and Autoimmune Diseasesmentioning

confidence: 99%

“…HF is a chronic and progressive condition that is characterized by the inability of the heart to pump an adequate supply of blood . Hauck et al have reported that MDM2 expression is significantly downregulated at the mRNA level in heart tissue samples from patients with idiopathic dilated cardiomyopathy (DCM), ischemic cardiomyopathy, and chemotherapy‐induced cardiomyopathy (Figure ). Similarly, acute cardiac‐specific ablation of MDM2 causes pathological cardiac hypertrophy and early death in an MDM2 f/f ; mcm conditional mutant mouse model .…”

Section: Roles Of Mdm2 In Hf and Cardiovascular Diseasesmentioning

confidence: 99%

“…Hauck et al have reported that MDM2 expression is significantly downregulated at the mRNA level in heart tissue samples from patients with idiopathic dilated cardiomyopathy (DCM), ischemic cardiomyopathy, and chemotherapy‐induced cardiomyopathy (Figure ). Similarly, acute cardiac‐specific ablation of MDM2 causes pathological cardiac hypertrophy and early death in an MDM2 f/f ; mcm conditional mutant mouse model . MDM2 affects cardiac growth by reducing p53 expression and increasing the expression of peroxisome proliferator‐activated receptor γ coactivator‐1α and PTEN‐induced kinase 1 .…”

Section: Roles Of Mdm2 In Hf and Cardiovascular Diseasesmentioning

confidence: 99%

“…Although its roles in malignancy and tumor progression have been the focus of most previous research, MDM2 has recently received increasing attention for its noncarcinogenic roles in various disorders and conditions, including inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure (HF) and cardiovascular diseases, nephropathy, diabetes, obesity, and fertility . As illustrated in Figure , MDM2 exerts its activity in both malignant and nonmalignant diseases by directly regulating diverse targets, for example, p53, p21, NFκB, and microtubule‐associated protein kinase (MAPK).…”

Section: Introductionmentioning

confidence: 99%

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Targeting MDM2 for novel molecular therapy: Beyond oncology

Wang

Qin

Rajaei

et al. 2019

Medicinal Research Reviews

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The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the bestdocumented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases,

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Section: Roles Of Mdm2 In Inflammation and Autoimmune Diseasesmentioning

confidence: 99%

Section: Roles Of Mdm2 In Hf and Cardiovascular Diseasesmentioning

confidence: 99%

Section: Roles Of Mdm2 In Hf and Cardiovascular Diseasesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting MDM2 for novel molecular therapy: Beyond oncology

Wang

Qin

Rajaei

et al. 2019

Medicinal Research Reviews

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“…The key finding of this study is that E3 ubiquitin ligase Mdm2 plays a direct role in mitophagy by regulating the activity of another E3 ubiquitin ligase, parkin, discovered via its genetic link to PD, as the name implies. Although the role of Mdm2 in mitochondria function was proposed earlier 66 , in that study Mdm2 appeared to act via ubiquitination of its well-established substrate, p53. Another reported mitochondria-related function of Mdm2 was not connected with p53 ubiquitination, involving instead its import into these organelles, where Mdm2 appears to repress the transcription of NADH-dehydrogenase 6, inhibiting respiratory complex I activity 51 .…”

Section: Discussionmentioning

confidence: 85%

Mdm2 enhances ligase activity of parkin and facilitates mitophagy

Kook

Zhan

Thibeault

et al. 2020

Sci Rep

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Loss-of-function mutations in the E3 ubiquitin ligase parkin have been implicated in the death of dopaminergic neurons in the substantia nigra, which is the root cause of dopamine deficit in the striatum in Parkinson's disease. Parkin ubiquitinates proteins on mitochondria that lost membrane potential, promoting the elimination of damaged mitochondria. Neuroprotective activity of parkin has been linked to its critical role in the mitochondria maintenance. Here we report a novel regulatory mechanism: another E3 ubiquitin ligase Mdm2 directly binds parkin and enhances its enzymatic activity in vitro and in intact cells. Mdm2 translocates to damaged mitochondria independently of parkin, enhances parkin-dependent ubiquitination of the outer mitochondria membrane protein mitofusin1. Mdm2 facilitates and its knockdown reduces parkin-dependent mitophagy. Thus, ubiquitously expressed Mdm2 might enhance cytoprotective parkin activity. The data suggest that parkin activation by Mdm2 could be targeted to increase its neuroprotective functions, which has implications for antiparkinsonian therapy.Parkin was first identified through its association with autosomal recessive juvenile parkinsonism, a familial form of Parkinson's disease (PD) with early onset 1 . Loss-of-function mutations in parkin gene, including exon deletions and rearrangements, as well as nonsense and missense mutations, are commonly associated not only with familial, but also with apparently sporadic early onset PD 2-5 . Functionally, parkin is an E3 ubiquitin ligase 6 . Initially, the studies of parkin function in PD concentrated on the search for parkin substrates and the role of parkin loss in the dysfunction of the ubiquitin-proteasome system (UBS), which appears to play a prominent role in the PD-related neurodegeneration 7 . Further studies implicated parkin in the regulation of the mitochondrial dynamics 8-10 . PINK1, another protein associated with a recessive form of early onset familial PD 11 , acts upstream of parkin, recruiting parkin to damaged mitochondria and stimulating its ligase activity 10,12-15 . Parkin then ubiquitinates proteins of the outer mitochondrial membrane causing their proteosomal degradation and elimination of the damaged mitochondria via mitophagy [16][17][18][19] . Mitochondrial dysfunction has been implicated in PD 20-23 , although the role of mitophagy in the quality control of neuronal mitochondria remains controversial [24][25][26] . Parkin exists in an autoinhibited basal state [27][28][29][30] . Its activity is regulated, in addition to the PINK1-dependent phosphorylation 15,31,32 , via a variety of mechanisms including formation of multiprotein signaling complexes [33][34][35] . Full spectrum of parkin interactions that regulate its activity is not yet understood. However, it is clear that this regulation is complex and often involves scaffolding proteins 36 , which may impact on parkin-dependent control of the mitochondrial dynamics and, consequently, its functions in the normal and diseased brain.We have recently de...

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