Drp1 is the main mitochondrial fission protein that is responsible for the cleavage of mitochondrial inner and outer membranes in mammals. Mutations in the GTPase domain can specifically cause alterations in the mitochondrial morphology and mitochondrial collapse [26]. Drp1 is proved to participate in the mitochondrial fission in mammalian cells as well as in C. elegans [27, 28]. Drp1 alone has the ability to constrict and sever cell membranes. Cutting requires the membrane binding, self-assembly and GTPase activity of Drp1, which plays the dominant role in the division of mitochondria and peroxisome [20]. Drp1 also plays a role in mitochondrial cristae remodeling mediated by the endoplasmic reticulum (ER) Ca${}^{2+}$ inflow and Drp1 recruitment to mitochondria [29].

The mitochondrial fission function of Drp1 is related to protein molecular modification and interactions. Norepinephrine (NE) mediated phosphorylation of Drp1 Ser-600 mediates the mitochondrial division and induces the mitochondrial uncoupling in brown adipose tissue (BAT), which results in increased heat production and energy expenditure. The mitochondrial division in BAT may be a novel potential therapeutic target to treat obesity [30]. In contrast, the hyperphosphorylation of Drp1 Ser-637 enhances the mitochondrial respiration by increasing mitochondrial fusion and lengthening mitochondria. Hyperphosphorylation of Drp1 Ser-637 also leads to increased mitochondrial proton gradient energy transfer, which increases the oxidative metabolism and prevented high-fat diet (HFD)-induced obesity [31]. Adipose tissue-specific DNA methyltransferase 1 (DNMT1) knockout blocks the interaction between enhancers and DRP1 by influencing DNA methylation, thereby inhibiting mitochondrial fission and leading to adipocyte hypertrophy and impaired expansion of adipocyte precursors. Loss of DNMT1 can lead to the damage of adipocyte $\beta$-oxidation, reduced membrane potential and mtDNA, and result in obesity in mice [32].

Induced by apoptosis, Drp1 is transferred to mitochondria and preferentially locates at potential sites of division [33]. Endoplasmic reticulum is reported to play a central role in Drp1 aggregation on mitochondria fission. Drp1 oligomerization can be transferred from ER to mitochondria or peroxisome by the communication between the ER and mitochondria [34]. Formin-like protein Inf2 mediates the Drp1 polymerization of ER, leading to the increased ER-mitochondrial contact. The increased endoplasmic reticulum calcium inflow to mitochondria causes the mitochondrial division [35, 36]. ER stress leads to diverse mitochondrial outcomes. Ablation of adipose tissue specific DRP1 leads to the failure of ER lipid droplets (LDs) release and shape change. Abnormal lipid droplets shape and accumulation during ER stress can further lead to mitochondrial dysfunction, lipolysis disorders, reduced thermogenesis, and finally defective systemic lipid metabolism [37]. In contrast, the deletion of hepatic DRP1 gene induces ER stress, and promotes the expression of fibroblast growth factor 21 (FGF21) in liver [38]. Increased expression of FGF21 and ER stress can lead to the increased energy expenditure in mice, thus playing a protective role in HFD-induced obesity [38, 39, 40]. Currently strong evidence shows that CerS6-derived sphingolipids promote Drp1-mediated mitochondrial fragmentation in obesity [41]. Ablation of CerS6 in a mouse model of HFD-induced insulin resistance facilitates a successful reversal of the fragmentation of hepatic mitochondrial network, rescues the insulin-sensitive phenotype and prevented HFD-induced obesity [42].

Reactive oxygen species (ROS) is considered as the mediator of mitochondrial fission in endothelial cells [43]. ER stress leads to the increased ROS production in adipocytes and decrease the catalase synthesis, thus affecting the lipid metabolism [44]. Besides, ROS acts as signal molecules to activate P38, a member of mitogen activated kinase-like protein (MAPK) family [45]. Obesity can increase the phosphorylation of P38 in the skeletal muscle, which is reversed by reduced mitochondrial fission due to DRP1 ablation [46]. Therefore, increased DRP1 expression increases the ROS level by inducing cell division, forming a vicious cycle that eventually leads to abnormal cell metabolism.

The dynamin-related GTPase Fis1 locates in the outer membrane of mitochondria and also induces the mitochondrial division [22, 47]. Fis1 recruits Drp1 from the cytoplasm to participate in the mitochondrial division, resulting in increased mitochondrial fragmentation and changed mitochondrial shape [48, 49]. Researches show that increased mitochondrial fission proteins Drp1 and Fis1 with decreased fission protein Mfn2 can lead to impaired mitochondrial function and oxidative stress [50]. Maternal obesity during pregnancy can reduce the expression of Fis1, Opa1, Mfn1, Mfn2 in offspring, resulting in reduced energy metabolism and fat utilization. Studies reveal that alteration of regulatory mitochondrial factors in offspring may lead to the impaired mitochondrial health and increased susceptibility to obesity later in life [51]. After mitochondrial fusion induced by silencing mitochondrial fission proteins including Fis1 and Drp1 in adipocytes, the content of triacylglycerol (TG) in adipocytes was reduced. It was speculated that the mitochondrial fusion may be more efficient in carrying out pyruvate dehydrogenation, oxidative phosphorylation and lipid metabolism [52]. A novel selective peptide inhibitor, P110, is reported to inhibits the Drp1/Fis1 interaction and production of ROS in cultured neurons. Thus, P110 is helpful with treatment of obesity [53].

As a component of the mitochondrial network, the dynamin-related protein Opa1, encoded by nuclear gene OPA1, plays a role in the mitochondrial aggregation and stabilization of inner membrane [54, 55, 56, 57]. Opa1 is located in the inner membrane of mitochondria and coordinates the mitochondrial cristae, which is essential in the mitochondrial respiratory chain and oxidative metabolism [58, 59, 60, 61]. Different isoforms of Opa1 play different roles. They can restore the cristae structure, mtDNA abundance and energy efficiency. The complete recovery of mitochondrial dynamic network requires the interaction of different Opa1 isoforms [62]. OPA1 gene inactivation leads to dramatic alterations in mitochondrial network, in which mitochondrial fragments are scattered, and the mitochondrial cristae is broken and disorganized [63].

Mitochondrial protease OMA1 zinc metallopeptidase (Oma1) can inactivate Opa1 under stress and inhibit mitochondrial fusion [64]. It has been proved that $\beta$-oxidation in the brown adipose tissue requires both Oma1 and Opa1 in mice. Oma1 deficient mice gradually gain weight with hepatic steatosis. Therefore, abnormal Oma1-Opa1 system may change the thermogenesis and metabolism of BAT, thus causing obesity [65]. Besides, Opa1 stabilizes respiratory chain supercomplexes (RSCs) to regulate the mitochondrial membrane potential to maintain the mitochondrial activity [66]. Mitochondrial proteins prohibitins (PHBs) act as scaffolds for mitochondrial inner membrane by forming multimeric ring complexes [67]. The latest research shows that interaction between the PHBs and Opa1 impairs the formation of mitochondrial RSCs and subsequently inhibits oxidative phosphorylation, and fatty acid $\beta$-oxidation (FAO), through unconventional interleukin-1 receptor (IL-1R)–MyD88 innate immune signal transduction adaptor (MyD88)–interleukin-1 receptor associated kinase 2 (IRAK2)–PHB/Opa1 pathway. Therefore, interleukin-1 (IL-1) induced chronic inflammation in obesity can reprogram the mitochondrial metabolism in adipocytes to exacerbate obesity [68].

Cardiolipin (CL), located in the inner membrane of mitochondria, is also important for the mitochondrial cristae stability. It has been reported that mitochondrial lipids, especially CL, play a major role in regulating the mitochondrial cristae shape and dynamics under PH changes [69, 70]. It has been discovered that carbohydrate response element-binding protein (ChREBP) KO mice are resistant to obesity, and recent research has found that is due to the combined influence of decreased CL synthesis and downregulated expression of Opa1 in brown adipose tissue (BAT). All of these two changes can cause abnormal mitochondrial cristae structure in BAT of ChREBP KO mice to display an anti-obese phenotype [71].

The stability of the mitochondrial cristae in different tissues also ultimately affects obesity. Recently it has been proved that adequate mitochondrial fusion and fission in neurons is important for metabolic regulation. In proopiomelanocortin (POMC) neurons, OPA1 gene inactivation leads to dramatic alterations in mitochondrial cristae topology, mitochondrial Ca${}^{2+}$processing, decreased lipolysis of WAT, and ultimately leading to obesity [72]. Besides, in muscle tissue, OPA1 deletion can cause non-lethal impaired electron transport chain and adenosine triphosphate (ATP) production due to the disrupted mitochondrial cristae structure. Activation of ER stress due to the OPA1 ablation may induce the secretion of FGF21 to reverse diet-induced obesity and insulin resistance [73].

The mitofusins (Mfn1 and Mfn2) lead to the mitochondrial fusion and regulate the mitochondrial cristae structure [74]. Both homomorphic and heteromorphic complexes work together to promote the mitochondrial outer membrane fusion in mammals [24, 75, 76, 77]. By influencing mitochondrial fusion, Mfn1 and Mfn2 regulate obesity-related metabolic changes such as reduced glucose oxidation, mitochondrial membrane potential, cellular respiration, and lipid toxicity [78, 79]. Enhanced mitochondrial fusion is beneficial to the mitochondrial biogenesis and lipid metabolism, which is impaired in obesity [78, 80, 81]. What’s more, decreased transcription of MFN2 gene is reported in obese humans, and the expression of MFN2 is negatively correlated with body mass index (BMI) [82]. Mutations in MFN2 (p.R104W, p.R707W) are found in obese patients [83, 84]. Broken mitochondrial networks and mitochondrial dysfunction with MFN2 mutations are speculated to cause inhibition of leptin expression and increase adipocyte proliferation and survival [85]. Moreover, selective deletion of MFN1 and MFN2 in mice impairs the mitochondrial fusion (both mitochondrial size and shape) in agouti-related protein (Agrp) neurons, resulting in impaired electrical activity of Agrp neurons, with increased resistance to fat gain and reduced weight gain in mice during high-fat diet [86]. Moreover, specific ablation of MFN2 in POMC neurons in the hypothalamus leads to loss of mitochondrial endoplasmic reticulum contact, resulting in endoplasmic reticulum stress, leptin resistance, hyperphagia, and reduced energy expenditure, which eventually lead to severe obesity [87].

The expression of mitochondrial fusion genes MFN1 and MFN2 is regulated by peroxisome proliferator-activated receptor $\gamma$ coactivator-1$\alpha$ (PGC-1$\alpha$) through synergistic activation of estrogen-associated receptor $\alpha$ [88, 89, 90]. PGC-1$\alpha$ promotes the transcription of MFN1 in mice, resulting in increased mitochondrial biogenesis and autophagy flux, which are impaired in obesity [91]. Moreover, PGC-1$\alpha$ can increase the level of heme oxygenase-1 (HO-1) to enhance the expression of MFN1 and MFN2, and then play a role in increasing the heat production, regulating the adipocyte differentiation, and improving the metabolic homeostasis [92, 93]. While decreased expression of PGC-1$\alpha$ and abnormal mitochondrial metabolism caused by mitochondrial dynamics disruption may promote lipid accumulation in cells [94]. Besides, leptin plays a role in inhibiting liver lipid deposition and improving hyperglycemia and hyperlipemia by increasing mitochondrial fusion-related transcription factors peroxisome proliferator-activated receptor $\alpha$ (PPAR$\alpha$), PGC-1$\alpha$ to up-regulate Mfn1 and Mfn2 [95].

In addition, Mfn2 dysfunction represses nuclear-encoded subunits of oxidative phosphorylation (OXPHOS) complexes I, II, III and V, thereby inhibiting pyruvate, glucose, and fatty acid oxidation and reducing mitochondrial membrane potential [81]. Mfn2 can also affect energy metabolism by regulating the interaction between lipid droplets and mitochondria [96]. Contact between activated mitochondria and lipid droplets will promote the transfer of fatty acids from lipid droplets to mitochondria for $\beta$-oxidation. Reduced Mfn2 expression levels in adipocytes may lead to reduced fatty acid transfer, thereby inhibiting fatty acid oxidation and facilitating fat storage [97]. MFN2 knockout can inhibit autophagose-lysosomal fusion, resulting in impaired autophagy degradation. Thus, mitochondrial respiration, ATP production, and cellular glycolysis are reduced, which affect the cellular biosynthesis and obesity [30, 98, 99]. A flavonoid compound derived from natural products named Vitexin is helpful in obesity treatment. Vitexin promotes the expression of Mfn2 and inhibits the expression of Drp1, thereby increasing mitochondrial membrane potential and alleviating the mitochondrial dysfunction [100].

Human membrane-associated RING-CH(March)-V/March5 is a novel mitochondrial outer membrane transmembrane protein. March5 plays a promoter role in the mitochondrial fusion [25]. March5 can bind Mfn2 to promote the formation of long tubular mitochondria and mitochondrial networks. It can also promote the ubiquitination of Drp1 to inhibit the mitochondrial division. March5 is regulated by peroxisome proliferator-activated receptor-$\gamma$ (PPAR$\gamma$) during adipogenesis. Knockout of MARCH5 leads to an increase in cellular glycolysis and basal mitochondrial respiration, as well as an increase in lipid uptake and synthesis [101].