However, another study showed that mitochondrial fusion also supported liver tumor cell growth [81]

However, another study showed that mitochondrial fusion also supported liver tumor cell growth [81]. quantity and morphology in response to metabolic and extracellular insults [5]. These fission and fusion events determine the shape of mitochondria and further influence their function. Mitochondrial dynamics contributes to the genesis and progression of various kinds of human being cancers [6]. Elucidating the part of mitochondrial dynamics in human being cancers is definitely of great importance, as this understanding will offer fresh insights into related treatments. After presenting a detailed description of protein mediators and lipids that have been acknowledged to regulate mitochondrial fusion and fission, this review focuses on summarizing fundamental cellular functions impacted by unbalanced fusion and fission. In addition, an overview of cancers including dysregulated mitochondrial dynamics is definitely presented in the third section. Rules of mitochondrial fusion and fission Mitochondrial dynamics is definitely exquisitely regulated by proteins and lipids (Number 1). Open in a separate window Number 1 A schematic diagram of mitochondrial dynamics. Human being mitochondria undergo constant fusion and fission dynamics. The fusion of the OMM is usually mediated by Mfn1/2. PA generated by MitoPLD promotes fusion of the OMM. CL and Opa1 coordinate IMM fusion. Mic60 also interacts with Opa1. ER tubules mark sites of fission. During mitochondrial fission, Drp1 is usually recruited to mitochondria by receptors such as Fis1, Mid49, Mid51 and Mff. GDAP1 and sacsin are two additional proteins localized in the OMM that facilitate fission. Drp1 activity is usually regulated by posttranslational modifications such as phosphorylation and ubiquitination. The preconstriction process is usually completed by actin filaments, and Drp1 performs mitochondrial scission. Lipids, including ceramides, PA and DAG, participate in mitochondrial fission. PA, phosphatidic acid; OMM, outer Methoxyresorufin mitochondrial membrane; CL, cardiolipin; Drp1, dynamin-related protein 1; DAG, diacylglycerol; ER, endoplasmic reticulum. Proteins involved in mitochondrial fusion In mammalian cells, the fusion machinery includes three essential GTPases, mitofusin (Mfn) 1 and 2 around the Methoxyresorufin outer mitochondrial membrane (OMM) and optic atrophy protein 1 (Opa1) around the Methoxyresorufin inner mitochondrial membrane (IMM) [7,8]. Mfn1 and Mfn2 coordinate OMM fusion. The c-terminal heptad repeats of Mfn1 and Mfn2 have been shown to form an intermolecular antiparallel coiled coil via which adjacent mitochondria may be drawn together and initiate mixing of their lipid bilayers, leading to fusion of the OMM [9]. Opa1 drives IMM fusion [10]. Opa1 is usually localized to the mitochondrial intermembrane space and the IMM. OPa1 has 8 isoforms, and the steady-state morphology of mitochondria depends on the balance of the long and short Opa1 isoforms [11]. Opa1 is likely to interact with Mfns to form intermembrane protein complexes that couple OMM fusion to IMM fusion [12]. The mitochondrial structural protein Mic60, also called mitofilin, appears to be a key Methoxyresorufin player in regulating mitochondrial shape [13]. Increased levels of Mic60 suppress mitochondrial fission in neurites, generating elongated neuritic mitochondria [14]. Mic60 also interacts with Opa1 [15]. MitoPLD belongs to the phospholipase D superfamily of signaling enzymes that generate phosphatidic acid (PA). MitoPLD is usually anchored to the mitochondrial surface [16], and MitoPLD-generated PA Amotl1 facilitates mitochondrial fusion [17]. Mitochondrial fission proteins Endoplasmic reticulum (ER) tubules contact mitochondria and mark the sites of mitochondrial division [18]. Several outer membrane proteins, including Mff, Fis1, Mid49 and Mid51, happen to be identified as dynamin-related protein 1 (Drp1) receptors [19-21]. Drp1 is usually recruited to the mitochondrial surface via its Methoxyresorufin transmembrane receptors and assembles into oligomeric complexes. Before the scission of mitochondria by Drp1, preconstriction is usually completed by actin and nonmuscle myosin II. A study reported that myosin II induced stochastic deformations of the interstitial actin network and exerted pressure on the mitochondrial surface, promoting mitochondrial fission [22]. The activity of Drp1 is usually regulated by posttranslational modifications. Several different posttranslational modifications of Drp1, including phosphorylation, ubiquitination and sumoylation, regulate its activity, thus influencing the fission process [23-26]. Moreover, human Fis1 was reported to regulate mitochondrial fission in the absence of Drp1. Fis1 binds to Mfn1, Mfn2 and Opa1, thus inhibiting their GTPase activity and the fusion machinery [27]. GDAP1 is usually another protein involved in mitochondrial fission events. This protein is usually localized in the OMM [28]. In animal models, neurons from GDAP1-knockout mice show large and defective mitochondria [29]. Sacsin localizes to the OMM in a variety of cell lines [30]. Loss of.