Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress

Dagda, Ruben K.; Zhu, Jianhui; Kulich, Scott; Chu, Charleen T.

doi:10.4161/auto.6458

Cited by 248 publications

(234 citation statements)

References 72 publications

(108 reference statements)

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“…For more information on mito-phagy, see Box 1. Moreover, recent evidence that points to mitochondrial localization of mitogene-activated protein kinase p42 as a key regulator for mitophagy convincingly demonstrates an important contribution of mitochondrial protein phosphorylation to mitophagy during cell stress [90]. In line with this assumption, parkinsonian-neurotoxin-induced mitophagy is dependent on MAPK signaling [91], and a yeast mitochondrial protein phosphatase homolog, Aup1p, that is similar to a family of protein phosphatase homologs in eukaryotic cells was described to be part of a signal-transduction mechanism that marks mitochondria for sequestration into autophagosomes [92].…”

Section: Mitophagy As a Potential Endpoint Of Lipotoxic Changes Aftermentioning

confidence: 99%

Mitochondrial protein phosphorylation: instigator or target of lipotoxicity?

Graier

Malli

Kostner

2009

Trends in Endocrinology & Metabolism

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Lipotoxicity occurs as a consequence of chronic exposure of non-adipose tissue and cells to elevated concentrations of fatty acids, triglycerides and/or cholesterol. The contribution of mitochondria to lipotoxic cell dysfunction, damage and death is associated with elevated production of reactive oxygen species and initiation of apoptosis. Although there is a broad consensus on the involvement of these phenomena with lipotoxicity, the molecular mechanisms that initiate, mediate and trigger mitochondrial dysfunction in response to substrate overload remain unclear. Here, we focus on protein phosphorylation as an important phenomenon in lipotoxicity that harms mitochondria-related signal transduction and integration in cellular metabolism. Moreover, the degradation of mitochondria by mitophagy is discussed as an important landmark that leads to cellular apoptosis in lipotoxicity. Mitochondrial relay functionThe term 'lipotoxicity' describes the dysfunction of non-adipose tissue and cells that face chronic exposure to elevated fatty acids, triglycerides and/or cholesterol [1][2][3]. When plasma levels of prandial and postprandial fatty acids, triglycerides or cholesterol exceed the uptake capacity of adipose tissue, non-adipose tissue becomes overloaded with lipids, resulting in several metabolic imbalances and/or diseases. Once the oxidative capacity of these cells is exhausted, lipotoxic pathways are initiated that yield cellular dysfunction and, at worst, result in cell death. Although multiple lipotoxic events have been described [1][2][3] (e.g. induction of endoplasmic reticulum stress [4,5] by disruption of its structural integrity [6]) recent findings point to mitochondrial dysfunction as a key phenomenon in lipotoxicity leading to ominous signals [7][8][9][10][11].The mitochondria not only serve as the power plant of the cell but also act as a cellular relay, sensing multiple cellular and environmental parameters, including energy status, oxygen availability and activation patterns of cellular signal-transduction pathways. Mitochondria then integrate these inputs, adapting their activity and functions to, ultimately, tune cellular responsiveness with respect to the current demand of the cell [12] (Figure 1). In spite of the important tasks of the mitochondrion and in contrast to its functions in energy metabolism, its contribution to signal transduction has not been thoroughly investigated, and the [24,25]. Because similar pathways were also described as leading to cellular differentiation [17], the actual physiological outcome might depend on the pattern of activated pathways rather than on a single phenomenon. Thus, it is feasible that changes in the mitochondrial phosphoproteome caused by alterations in kinase activities are fundamental for the decisive setting of signaling patterns for cell survival or the initiation of cellular dysfunction in lipotoxicity leading to cell death. Three different scenarios affecting mitochondrial protein phosphorylation can be postulated in lipotoxicity ( Figure ...

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Section: Mitophagy As a Potential Endpoint Of Lipotoxic Changes Aftermentioning

confidence: 99%

Mitochondrial protein phosphorylation: instigator or target of lipotoxicity?

Graier

Malli

Kostner

2009

Trends in Endocrinology & Metabolism

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“…Next, we assessed cellular levels of Beclin 1, an established component of the autophagic machinery (Cao and Klionsky, 2007), in the tetraspanin vs mock-transfected MM cell lines, but failed to determine significant changes (data not shown). Interestingly, several recent publications present evidence of a 'Beclin-independent autophagic pathway' distinguished with an ERK and/or JNK-induced autophagy (Chu et al, 2007;Dagda et al, 2008). Therefore, we examined the importance of ERK and JNK signalling to transfected MM cells.…”

Section: Autophagic Death Induced By Cd81n1 and Cd82n1 In MM Cell Linesmentioning

confidence: 99%

Tetraspanin-induced death of myeloma cell lines is autophagic and involves increased UPR signalling

et al. 2009

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BACKGROUND: Multiple myeloma (MM) therapy is hindered by the interaction of the heterogeneous malignant plasma cells with their microenvironment and evolving drug resistance. We have previously shown that the membranal tetraspanins, CD81 and CD82, are under-expressed in MM cells and that their reintroduction causes massive non-apoptotic death. In this study, we aimed to characterise the tetraspanin-induced MM death. METHODS: Multiple myeloma cell lines were transiently transfected with eGFP -CD81N1/CD82N1 fusion proteins and assessed for death mode by flow cytometry (propidium iodide, ZVAD-fmk, 3MA), activation of unfolded protein response (UPR), and autophagy (immunoblot, RT -PCR). RESULTS: Cell death induced by CD81N1 and CD82N1 in MM cell lines was autophagic and involved endoplasmic reticulum (ER)-stress manifested by activation of UPR pathways, PERK (protein kinase-like ER kinase) and IRE1 (inositol-requiring 1). We also established the relative X-box binding protein 1 baseline expression levels in a panel of MM cell lines and their general dependence on autophagy for survival. Timeline of UPR cascades and cell fate supported our results. INTERPRETATION: This is the first publication implicating tetraspanins in UPR signalling pathways, autophagy, and autophagic death. Integration of our findings with published data highlights the unifying dependence of MM cells on ER -Golgi homoeostasis, and underscores the potential of tetraspanin complexes and ER-stress as leverage for MM therapy.

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“…Although inclusion of mitochondria in autophagosomes was once believed to be a random process, as observed during starvation, studies involving hypoxia, mitochondrial damage, apoptotic stimuli, or limiting amounts of aerobic substrates in facultative anaerobes support the concept of selective mitochondrial autophagy (mitophagy) (29,30). In particular, mitochondrially localized kinases may play an important role in models involving oxidative mitochondrial injury (25,31,32).…”

mentioning

confidence: 99%

“…Interestingly, mitochondrial fission accompanies autophagic neurodegeneration elicited by the PD neurotoxin 6-OHDA (24,25). Moreover, mitochondrial fragmentation and increased autophagy are observed in neurodegenerative diseases including Alzheimer and Parkinson diseases (4, 26 -28).…”

mentioning

confidence: 99%

“…Recently, Parkin, which complements the effects of PINK1 deficiency on mitochondrial morphology (3), was found to promote autophagy of depolarized mitochondria (39). Conversely, Beclin 1-independent autophagy/mitophagy contributes to cell death elicited by the PD toxins 1-methyl-4-phenylpyridinium and 6-OHDA (25,28,31,32), causing neurite retraction in cells expressing a PD-linked mutation in leucine-rich repeat kinase 2 (40). Whereas properly regulated autophagy plays a homeostatic and neuroprotective role, excessive or incomplete autophagy creates a condition of "autophagic stress" that can contribute to neurodegeneration (28).…”

mentioning

confidence: 99%

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