Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells

Chen, Hsiuchen; Chan, David C.

doi:10.1016/j.cmet.2017.05.016

Cited by 355 publications

(340 citation statements)

References 101 publications

(145 reference statements)

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“…The phospho‐manipulation of the complex I subunits ultimately promoted the respiration necessary to produce the bioenergetic currency necessary for cell division . Both the regulation of mitochondrial fission and respiratory chain by Cdk1/cyclin B have been linked to oncogenesis and therapeutic resistance in brain tumors as well as other types of cancer . Collectively, mitochondrial signaling by Cdk1/cyclin B is an excellent example of the extensive coordination between mitochondrial and cellular programming.…”

Section: Other Kinases Associated With Ommmentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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Section: Other Kinases Associated With Ommmentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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“…Conversely, inhibition of fission and/or stimulation of fusion leads to mitochondrial elongation. An aberrant balance between fission and fusion has been observed in a number of human diseases and impacts a broad range of cellular functions (Ong & Hausenloy, ; Romanello et al , ; Yoon et al , ; Rehman et al , ; Youle & van der Bliek, ; Schrepfer & Scorrano, ; Chen & Chan, ; Trotta & Chipuk, ).…”

Section: Introductionmentioning

confidence: 99%

Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery

et al. 2019

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Mitochondrial dynamics is important for life. At center stage for mitochondrial dynamics, the balance between mitochondrial fission and fusion is a set of dynamin‐related GTP ases that drive mitochondrial fission and fusion. Fission is executed by the GTP ases Drp1 and Dyn2, whereas the GTP ases Mfn1, Mfn2, and OPA 1 promote fusion. Recruitment of Drp1 to mitochondria is a critical step in fission. In yeast, Fis1p recruits the Drp1 homolog Dnm1p to mitochondria through Mdv1p and Caf4p, but whether human Fis1 ( hF is1) promotes fission through a similar mechanism as in yeast is not established. Here, we show that hF is1‐mediated mitochondrial fragmentation occurs in the absence of Drp1 and Dyn2, suggesting that they are dispensable for hF is1 function. hF is1 instead binds to Mfn1, Mfn2, and OPA 1 and inhibits their GTP ase activity, thus blocking the fusion machinery. Consistent with this, disruption of the fusion machinery in Drp1 −/− cells phenocopies the fragmentation phenotype induced by hF is1 overexpression. In sum, our data suggest a novel role for hF is1 as an inhibitor of the fusion machinery, revealing an important functional evolutionary divergence between yeast and mammalian Fis1 proteins.

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“…OPA1 undergoes proteolytic processing leading to the balanced accumulation of short (S‐) and membrane‐anchored long forms (L‐) of OPA1 (MacVicar & Langer, ). Whereas either L‐OPA1 or S‐OPA1 is sufficient to preserve cristae structure and respiration (Anand et al , ; Del Dotto et al , ; Lee et al , ), L‐OPA1 is required to mediate mitochondrial fusion (Tondera et al , ; Ban et al , ; Chen & Chan, ). Two IM proteases can cleave L‐OPA1 at neighboring sites and limit fusion: the stress‐activated peptidase OMA1 (Ehses et al , ; Head et al , ) and the ATP‐dependent i ‐AAA protease YME1L (Griparic et al , ; Song et al , ).…”

Section: Introductionmentioning

confidence: 99%

Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

et al. 2018

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Disturbances in the morphology and function of mitochondria cause neurological diseases, which can affect the central and peripheral nervous system. The i‐AAA protease YME1L ensures mitochondrial proteostasis and regulates mitochondrial dynamics by processing of the dynamin‐like GTPase OPA1. Mutations in YME1L cause a multi‐systemic mitochondriopathy associated with neurological dysfunction and mitochondrial fragmentation but pathogenic mechanisms remained enigmatic. Here, we report on striking cell‐type‐specific defects in mice lacking YME1L in the nervous system. YME1L‐deficient mice manifest ocular dysfunction with microphthalmia and cataracts and develop deficiencies in locomotor activity due to specific degeneration of spinal cord axons, which relay proprioceptive signals from the hind limbs to the cerebellum. Mitochondrial fragmentation occurs throughout the nervous system and does not correlate with the degenerative phenotype. Deletion of Oma1 restores tubular mitochondria but deteriorates axonal degeneration in the absence of YME1L, demonstrating that impaired mitochondrial proteostasis rather than mitochondrial fragmentation causes the observed neurological defects.

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Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells

Cited by 355 publications

References 101 publications

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery

Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

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