Extracellular Regulated Kinase Phosphorylates Mitofusin 1 to Control Mitochondrial Morphology and Apoptosis

Pyakurel, Aswin; Savoia, Claudia; Heß, Daniel; Scorrano, Luca

doi:10.1016/j.molcel.2015.02.021

Cited by 192 publications

(142 citation statements)

References 52 publications

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“…In this study, Drp1 inhibition rescued sensitivity to apoptotic stimuli by restoring a balanced mitochondrial network (Renault et al, 2015). Additionally, Mfn1 is a target of the MEK/ERK signaling pathway - phosphorylated Mfn1 inhibits mitochondria fusion and interacts with BAK to stimulate its oligomerization and subsequent MOMP (Pyakurel et al, 2015). Therefore, while fission and fusion do not necessarily regulate apoptosis per se, a balance of these activities appears to generate a mitochondrial shape that supports interactions with pro-apoptotic Bcl2 proteins.…”

Section: Cell Deathmentioning

confidence: 99%

Mitochondria and Cancer

Vyas

Zaganjor

Haigis

2016

Cell

1,340

1,065

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Mitochondria are bioenergetic, biosynthetic and signaling organelles that are integral in stress sensing to allow for cellular adaptation to the environment. Therefore, it is not surprising that mitochondria are important mediators of tumorigenesis, as this process requires flexibility to adapt to cellular and environmental alterations in addition to cancer treatments. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation including mitochondrial biogenesis and turnover, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. Thus, understanding mechanisms of mitochondrial misregulation during tumorigenesis will be critical for the next generation of cancer therapeutics.

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Section: Cell Deathmentioning

confidence: 99%

Mitochondria and Cancer

Vyas

Zaganjor

Haigis

2016

Cell

1,340

1,065

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“…For example, tBID is better recruited and undergoes conformation changes in membranes with cardiolipin (Shamas-Din et al, 2015). Not only does mitochondrial lipid composition influence apoptosis, but mitochondria morphology and size can also determine sensitivity to MOMP (Pyakurel et al, 2015; Renault et al, 2015). Finally, a recent study indicates that mitochondrial interactions with the endoplasmic reticulum can result in mitochondria inner membrane remodeling downstream of BAX and BAK activation and efficient cytochrome c release (Prudent et al, 2015).…”

Section: The Composition Structure and Subcellular Location Of Mitocmentioning

confidence: 99%

Mitochondria—Judges and Executioners of Cell Death Sentences

2016

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Apoptosis is a form of programmed cell death that is critical for basic human development and physiology. One of the more important surprises in cell biology in the last two decades is the extent to which mitochondria represent a physical point of convergence for many apoptosis inducing signals in mammalian cells. Mitochondria not only adjudicate the decision of whether or not to commit to cell death, but also release toxic proteins culminating in widespread proteolysis, nucleolysis, and cell engulfment. Interactions among Bcl-2 family proteins at the mitochondrial outer membrane controls the release of these toxic proteins, and by extension control cellular commitment to apoptosis. This pathway is particularly relevant to cancer treatment, as most cancer chemotherapies trigger mitochondrial mediated apoptosis. In this review, we discuss recent advances in the Bcl-2 family interactions, their control by upstream factors, and how the mitochondria itself alters these interactions. We also highlight recent clinical insights into mitochondrial mediated apoptosis and novel cancer therapies that exploit this pathway. Introduction Mitochondria adjudicate the cell death decision in response to many physiological and therapeutic stimuli. The review we highlight seminal and recent advances on how mitochondria and the Bcl-2 family of proteins regulate cell death. In particular we discuss recent advances in the Bcl-2 family interactions, their control by upstream factors, and how the mitochondria itself alters these interactions. We also highlight recent clinical insights into mitochondrial mediated apoptosis and how cancer therapies that exploit this pathway.

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“…Furthermore, phosphorylation of Mfn2 at S27 can activate ubiquitin-mediated degradation of Mfn2 during cellular stress, leading to mitochondrial fission and apoptosis in cells of the U-2 OS cell line (Leboucher et al, 2012). Phosphorylation of Mfn1 by ERK2 (also known as MAPK1) inhibits Mfn1 oligomerization, thereby promoting mitochondrial fission and apoptosis (Pyakurel et al, 2015). Besides phosphorylation, acetylation of Mfn1 triggers its degradation during cellular stress through ubiquitylation mediated by the E3 ligase MARCH5 .…”

Section: Post-translational Regulation Of Mitochondrial Fission and Fmentioning

confidence: 99%