Introduction

Nonalcoholic fatty liver disease (NAFLD) has been identified as a global epidemic and it is mostly likely to occur in association with type 2 diabetes and obesity (Milic and Stimac 2012; Loomba and Sanyal 2013). NAFLD constitutes a spectrum of liver disorders that begins with simple steatosis (SS), which can progress to nonalcoholic steatohepatitis (NASH), nonalcoholic steatofibrosis (NASF), cirrhosis, and hepatocellular carcinoma (HCC) in advanced stages (Younes and Bugianesi 2019).

Insulin resistance, oxidative stress, and inflammation are believed to play central roles in the pathogenesis of NAFLD (Lewis and Mohanty 2010). Despite an understanding of how lipid accumulates in the liver (SS), the mechanisms by which NASH and NASF develop are unclear. Numerous hypotheses have been proposed for NAFLD pathogenesis. According to the classical “two-hit” hypothesis, NAFLD is a sequential disease whereby insulin resistance (“the first hit”) promotes an increased flux of free fatty acids (FFAs) into hepatocytes. If these FFAs are not appropriately metabolized or secreted, simple steatosis can develop (Day and James 1998). Simple steatosis then predisposes the liver to a “second hit” including mitochondrial dysfunction, ER stress, bacterial endotoxins of intestinal origin, and inflammation. This classical hypothesis has been modified to indicate that NAFLD may be a consequence of parallel “multi-hits” (Tilg and Moschen 2010). In this model, insulin resistance results in increased lipogenesis and excessively elevated uptake of FFAs into hepatocytes. This lipotoxicity primes the liver for injury arising from “multiple and parallel hits” (oxidative stress and the activation of proinflammatory and fibrogenic pathways including the activation of Kupffer cells and hepatic stellate cells), which leads to NASH and NASF (Berlanga et al. 2014).

Mitochondria are key organelles that play a vital role in energy generation from glucose, glutamine and lipid metabolism. Alterations in mitochondrial structure and function are considered a hallmark of NAFLD. Early observations in patient with NASH described the presence of dysfunctional mitochondria in hepatocytes (Garcia-Ruiz et al. 2013). Moreover, studies in experimental models have shown a wide range of changes in mitochondrial functions (Sunny et al. 2017). Besides their function in ATP generation by oxidative phosphorylation, mitochondria also plays important roles in many other cellular events, including fatty acid breakdown by β-oxidation, the synthesis of ketone bodies, the oxidative catabolism of amino acids, metabolite production via the tricarboxylic acid cycle (TCA cycle), and the generation of reactive oxygen species (ROS) (Kelly and Scarpulla 2004; Murgia et al. 2009; Murphy 2009). Hence, alterations in mitochondrial function may have a broad impact on cellular integrity and thus stand out as an important mechanism underlying the pathogenesis of NAFLD. The aim of this review is to provide a general overview of mitochondrial perturbations in terms of energy metabolism and their potential implications in NAFLD.

Mitochondria dysfunction in NAFLD: oxidative stress and ROS production

Under conditions of normal mitochondrial homeostasis, a cell can effectively remove physiological ROS through antioxidant mechanisms as well as by enabling metabolic adaptations that inhibit substrate delivery to the TCA cycle, a series of enzyme-catalyzed chemical reactions used by aerobic organisms to release energy. In NAFLD, however, both increased mitochondrial ROS production and decreased activity of ROS scavenging mechanisms (e.g., GSH, SOD2, and catalase) could potentiate the effects of oxidative stress through oxidization of polyunsaturated fatty acids, leading to the production of aldehyde by-products such as 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA) (Yin et al. 2015). Also, oxidative stress induces protein oxidation and lipid peroxidation promoting alterations in the mitochondrial genome. These mechanisms may eventually result in a deleterious cycle of mitochondrial damage and mitochondria-originating oxidative stress (Mantena et al. 2009).

Clinically, liver tissues from patients with NASH have high mitochondrial levels of ROS and ROS-mediated mitochondrial DNA (mtDNA) damage (Pessayre 2007). Similarly, hepatic tissues from obese (ob/ob) mice have been shown to have increased levels of lipogenesis from glucose (Kaplan and Leveille 1981, Begriche et al. 2010), an increased formation of mitochondrial ROS, higher levels of oxidative stress, enhanced lipid peroxidation, reduced levels of mitochondrial ETC components (Larosche et al. 2010), and decreased ATP levels (Chavin et al. 1999; Lin et al. 2000; Begriche et al. 2010). Compared with normal liver, fatty livers from ob/ob mice have increased levels of tumor necrosis factor (TNF) (Lin et al. 2000; Begriche et al. 2006) and FFAs, and a higher degree of proton leakage, which results in a decrease in ATP synthesis (Begriche et al. 2010).

Since patients with NAFLD have elevated mitochondrial fatty acid oxidation (FAO) and the TCA cycle, increased supply of reducing equivalents to the electron transport chain is sustained. This prolonged dysfunction in the respiratory complexes promotes the production of superoxide (Aharoni-Simon et al. 2011) (Fig. 1). Additionally, ROS driven mitochondria dysfunction has been reported to activate adenosine monophosphate–activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK), which are known to be mitogen-activated protein kinases (MAPKs) (Meakin et al. 2014; Herzig and Shaw 2018; Win et al. 2018). Activation of these signaling pathways plays a critical role in the development of liver diseases and injuries, such as steatosis, NASH, fibrosis, and HCC (Tilg and Moschen 2010; Lewis and Mohanty 2010; Quinlan et al. 2013).

Fig. 1
figure 1

Effects of oxidative stress and ROS on mitochondria. In the fatty liver of patients with NAFLD, mitochondria are exposed to prolonged oxidative stress and increased fatty acid oxidation and flux through the TCA cycle. This eventually leads to dysfunction in the ETC and the increased production of ROS. Increased production of ROS has a deleterious effect on mitochondria by causing the conversion of superoxide to hydrogen peroxide, which induces a stress signaling response and mitochondrial damage. Also, long exposure to oxidative stress impairs DNA repair system of mitochondria. As a result, detrimental effects, such as malfunction in nuclear DNA, a depletion of mtDNA, and increased levels of 8-hydroxy-2′-deoxyguanosine. In addition to these deleterious effects in mitochondria, increased ROS production also activate the AMPK, JNK, and MAPK pathways to cause serious injury in hepatocytes

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While mitochondria have been known to be the major site of ROS production in the cell, complex I and III are considered to be major sites of superoxide production (Tell et al. 2013; Kotiadis et al. 2014). More recent studies have demonstrated that other mitochondrial enzymes are also associated with a decline in mitochondrial homeostasis. Both glycerol 3-phosphate dehydrogenase and 2-oxoglutarate dehydrogenase have been suggested to be involved in maintaining mitochondrial redox potent (Quinlan et al. 2013). An enzyme called superoxide dismutase converts superoxide into hydrogen peroxide which can then cause mitochondrial damage and/or initiate stress signaling responses.

As mitochondrial enzyme contributes to destruction of mitochondrial homeostasis, cardiolipin, a unique phospholipid found in the inner mitochondrial membrane, is highly sensitive to oxidative stress, resulting in mitochondrial dysfunction that includes the loss of ETC complex activity and the induction of mitochondrial permeability transition (MPT) pore opening (Li et al. 2010). Furthermore, cytochrome c, which is released from cardiolipin into the cytosol can activate the caspase-mediated apoptotic pathway leading to subsequent cell death (Kagan et al. 2005). Aside from inner mitochondria membrane, elevated ROS production have been suggested to be linked with mitochondrial outer membrane permeabilization (MOMP), altered mitochondrial membrane potential (ΔΨm), and a loss of mitochondrial integrity in NAFLD (Rector et al. 2010).

Along with mitochondria membrane’s permeability destruction, accumulating evidence suggests that oxidative stress can cause alterations in mtDNA. MtDNA is particularly susceptible to oxidative damage due to the fact that it is immediately adjacent to the site of ROS production and DNA repair systems. NAFLD is characterized by both mtDNA depletion and increased levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), an oxidized form deoxyguanosine. In addition, oxidative damage of nuclear DNA may also ultimately lead to mitochondrial dysfunction by compromising the transcription of nuclear-encoded mitochondrial genes. For example, the expression levels of critical factors involved in mitochondrial metabolism and biogenesis such as TFAM, NRF-2, and PGC-1α, have been reported to be decreased in NAFLD (Aharoni-Simon et al. 2011). Thus, the mechanisms for mitochondrial alterations and inadequate adaptation have strong connection with changes in mitochondrial ROS formation and subsequent ROS signaling, which ultimately cause dysfunctions in mitochondrial biogenesis and mitophagy (Table 1). These alterations also regulate changes in mitochondrial levels of GSH, FFAs, and lipid peroxidation products.

Table 1 Mitochondrial dysfunction-mediated NAFLD development
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Mitochondrial quality control: mitophagy in NAFLD

Changes in morphology of mitochondria is very critical for long-term viability of cell. These cellular events, which are also known as the mitochondrial fission and fusion, is controlled by different molecules (e.g., MFN2, OPA1, and DRP1) (Table 2). Along with mitochondrial morphology control, mitophagy is the selective degradation of damaged mitochondria through autophagy. Mitophagy has recently suggested to play a key role in NAFLD. In the pathogenies of NAFLD, ALCAT1, a lysocardiolipin acyltransferase that catalyzes the pathological remodeling of cardiolipin, can cause mitochondrial dysfunction, including inhibition of mitophagy and OXPHOS (Wang et al. 2015). Recently, p62 has been found to promote mitochondrial ubiquitination and mitophagy through the recruitment of two subunits of a cullin-RING ubiquitin E3 ligase complex, Keap1 and Rbx1, protecting against the development of NAFLD (Yamada et al. 2018). AMPK is important in preventing hepatic lipid accumulation and inflammation (Day et al. 2017). AMPK can induce mitophagy through a dual mechanism involving both the activation of ULK1 and suppression of the mammalian target of rapamycin (mTOR) complex (Egan et al. 2011). Given that mitochondrial fission is required for the induction of mitophagy (Tanaka et al. 2010), it is intriguing that AMPK-mediated fission is induced by the mitochondrial fission factor, a mitochondrial outer-membrane receptor for DRP1 (Toyama et al. 2016).

Table 2 Mitochondrial quality control-mediated NAFLD development
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The role of mitochondria in the development of simple steatosis

High-caloric fat diets can cause the dysregulation of lipid and glucose metabolism, resulting in the accumulation of triglycerides (TGs) and free fatty acids (FFAs) in the liver (Eccleston et al. 2011). Under these circumstances, hepatic metabolism is shifted to allow recovery from the hepatic lipid burden. This shift includes increased FAO, followed by induction of the tricarboxylic acid (TCA) cycle and enhanced oxidative phosphorylation (OXPHOS) (Sunny et al. 2011). AMPK activates catabolic pathway such as fatty acid and glucose oxidation pathways by inducing the activation of PGC-1〈 (Meakin et al. 2014; Herzig and Shaw 2018). PGC-1〈 interacts with peroxisome proliferator–activated receptor 〈 (PPAR〈) to induce the expression of several enzymes involved in fatty acid-metabolism, including carnitine palmitoyltransferase-1 (CPT-1) and acyl-CoA dehydrogenases, ultimately promoting mitochondrial fatty acid ®-oxidation (Fromenty and Pessayre 1995; Pessayre et al. 2012). CPT-1 catalyzes the import of FFAs into the mitochondria. CPT-1 is inhibited by malonyl-CoA (Pessayre et al. 2001; Gusdon et al. 2014) which is formed by acetyl-CoA carboxylase during the initial step in the synthesis of FFAs from acetyl-CoA (Gusdon et al. 2014; Meakin et al. 2014). Excess levels of carbohydrates result in the increased production of acetyl-CoA, subsequently leading to the inhibition of CPT-1 and ultimately and inhibition of ®-oxidation (McGarry and Foster 1980; Fromenty and Pessayre 1995; Pessayre et al. 2002; Gusdon et al. 2014). Activation of CPT-1 can inhibit liver injury in patient with NAFLD as demonstrated by decreased serum levels of AST, ALT, bilirubin, and mtDNA (Lim et al. 2010). This entire process precisely regulates mitochondrial energy metabolism in the liver of healthy individuals, but not in the liver of patient with NAFLD (Larosche et al. 2007; Babbar and Sheikh 2013; Gusdon et al. 2014; Sunny et al. 2017).

Mitochondrial contribution to the transition from simple steatosis to NASH and NASF

Liver biopsies from patient diagnosed with NASH and obesity have shown ultrastructural damage to the mitochondria (Sanyal et al. 2001; Hinke et al. 2007). Even with exposure to oxidative stress and ROS, there is continuous mitochondrial adaptation on morphology (mitochondrial fission and fusion), dynamics of energy expenditure and gene expression, which are also known as mitochondrial ‘remodeling’ (Sunny et al. 2017). In NAFLD, increased FFAs and de novo lipogenesis, and accumulation of TGs induce adaptations of mitochondrial oxidative metabolism, for instance increased hepatic TCA cycle due to following failure of cellular functions: incomplete β-oxidation, impairment of ketogenesis, and decreased mitochondrial respiratory chain and ATP synthesis (Sunny et al. 2017). Despite the efforts of the liver to overcome lipid accumulation, the mitochondrial adaptative response is insufficient to protect against lipotoxicity due to the continuous and chronic deposition of FFAs. This phenomenon has been demonstrated in a choline-deficient NAFLD mouse model, which showed that there were higher levels of mitochondrial biogenesis and mitochondrial mass in fatty livers in the early stage of disease than in liver tissue from healthy animals (Babbar and Sheikh 2013; Mansouri et al. 2018). At later times, mitochondrial dysfunction manifest as alterations in the ETC complexes and membrane potential (Δψm), and decreased ATP synthesis (Teodoro et al. 2008). Consequently, the capacity of mitochondria to overcome the increased import of FFAs is lost in the more advanced stages of NAFLD. Moreover, in later stages, disease progression is accelerated by inhibition of CPT-1, impaired mitochondrial FAO, and chronic ATP depletion caused by the increased hepatic expression of UCP2 (Serviddio et al. 2008). These findings suggest that the ability of mitochondria to adapt to increased FFAs seen in the early stages of NAFLD development (simple steatosis) decreases as NAFLD progresses to NASH.

All NASH etiologies are linked with the increased formation of mitochondrial ROS (Tell et al. 2013). Generally, oxidative stress and lipid peroxidation have been reported to activate NF-κB to induce the production of pro-inflammatory cytokines (TNF-α, IL-1β, Il-6 and IL-8), which cause apoptosis and necrosis in hepatocytes (Pessayre et al. 2001, 2002; Carter-Kent et al. 2008; Tell et al. 2013; Rodrigues et al. 2017). This mitochondria-associated vicious cycles may include lipid accumulation, lipid peroxidation, ROS formation, depletion of antioxidants, altered mitochondrial quality control, and mitochondrial damage-induced inflammation (Larosche et al. 2007; Pessayre 2007; Zhang et al. 2010; Begriche et al. 2011; Marques et al. 2012; Tell et al. 2013; Feillet-Coudray et al. 2014; Marques et al. 2015). Damaged mitochondria and the subsequent necrosis of hepatocytes produce mitochondria-derived danger associated molecular patterns (DAMPs) (Fig. 2). Mitochondria possess bacteria-like characteristics, including the presence of hypomethylated CpG motifs in the mitochondrial genome, formylpeptides, and other danger signals. These mitochondrial DAMPs activate NOD like receptor family pyrin domain contain 3 (NLRP3) inflammasome and other innate immune system via pattern recognition receptors such as TLRs (Murgia et al. 2009; Murphy 2009; Elsheikh et al. 2010; Marques et al. 2015). For example, once released from damaged hepatocytes in HFD-fed mice, mtDNA has been shown to interacts with the TLR9 on Kupffer cells and hepatic stellate cells to stimulate the innate immune and fibrogenic responses, as has been suggested to occur in the pathogenesis of NASH (Begriche et al. 2006; Murgia et al. 2009; Murphy 2009; Garcia-Martinez et al. 2016). Finally, ROS-associated lipid peroxidation, mitochondrial DAMPs, and subsequent activation of caspases establish chronic liver injury by the infiltration of inflammatory cells (Pessayre et al. 2002; Murgia et al. 2009; Tell et al. 2013; Handa et al. 2014).

Fig. 2
figure 2

Mitochondria-mediated mechanisms of steatohepatitis and fibrosis in the pathogenesis of NAFLD. The increased accumulation of damaged/dysfunctional mitochondria within hepatocyte results in cell necrosis and induces the leakage of mitochondrial DAMPs, such as mtDNA, N-formyl peptides, and ATP. These signals subsequently trigger the activation of Toll-like receptor 9 (TLR9) and formyl peptide receptor 1 (FPR1), which in turn activates the IRFs and NF-kB, and thereby the production of inflammatory cytokines. mtDNA and ATP also activate the inflammasomes NLRP3 and AIM2, respectively. Multiple inflammatory cytokines and the activation of inflammasomes provide a chronic inflammatory milieu, which contributes the development of steatohepatitis and fibrosis

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The levels of microRNA miR-21 have been reported to be increased in the liver of human patients and mice with NASH, and in whom caspase-2 is activated (Rodrigues et al. 2017). The mTOR/NF-κB pathway-mediated miR-21 activation inhibits PPAR-α and promotes mitochondrial dysfunction and hepatocyte injury. In addition, miR-26a, miR-33a and miR-141-3p have been found to regulate mitochondrial function in the pathogenesis of NAFLD. miR-26a overexpression protects against hepatocyte apoptosis and regulates fatty acid and cholesterol homeostasis (Ali et al. 2018). miR-33a specifically inhibits mitochondrial complex I activity and its knockdown protected HFD-induced mitochondrial dysfunction (Nie et al. 2018). miR-141-3p is dramatically up-regulated in HFD-fed mice and could promotes mitochondrial dysfunction by inhibition of phosphatase and tensin homolog (PTEN) (Ji et al. 2015). Cell death caused opening of the MPT pore which seems to be a critical event in hepatocyte cell death (Chavin et al. 1999).

Moreover, ER stress plays critical factors in the pathogenesis of NAFLD as aggregation of unfolded protein response (UPR) causing ER stress is required for hepatic lipid metabolism as protective stress response (Henkel and Green 2013). Comparing levels of ER stress related transcriptions factors such as activating transcription factor 6 (ATF6), X-box–binding protein 1 (XBP1 s) and C/EBP homologous protein (CHOP), liver tissue from patients with NAFLD and NASH have higher expression compared to normal individuals’ liver tissue (Lee et al. 2017a, b). ER chaperons (e.g., GRP78 and GRP94), which takes huge role in mediating protein misfolding were downregulated in liver tissue from patient diagnosed with NAFLD and NASH compared to normal liver tissue (Lee et al. 2017a, b). Mitochondrial dysfunction in NASH also decreases ATP synthesis, which may cause endoplasmic reticulum (ER) stress and activation of the UPR. The UPR is linked to the activation of de novo lipogenesis and further enhances the development of steatosis (Lee et al. 2017a, b). Recent studies have demonstrated that prolonged ER stress, or chronic activation of the UPR, also induces hepatocyte injury and inflammation through a CHOP-dependent signaling pathway (Willy et al. 2015). Moreover, the mis folding of apoB protein, a major component of very-low density lipoprotein (VLDL), impairs lipid export from the liver and exacerbates steatosis in mice (Uchiyama et al. 2006).

Increased mitochondrial cholesterol accumulation is also associated with the transition from steatosis to NASH. In patient with NASH, the cholesterol content has been shown to be negatively correlated with mitochondrial GSH (mtGSH) levels (Gan et al. 2014). Decreased mt GSH levels may arise as a result of damage to the mtGSH transport system, which transports GSH from the cytosol to mitochondria as well as causes alterations in their membrane permeability upon induction by high cholesterol level. High levels of cholesterol have also been found to sensitize hepatocytes to TNF- and Fas-induced apoptosis and to cause mitochondrial GSH depletion in ob/ob mice (Mari et al. 2006).

Clinical research findings involving mitochondria-mediating drugs

Clinical trials have been conducted to evaluate the efficacy of several drug candidates in patient with NAFLD. Metformin and pioglitazone are generally recommended for treatment in select NAFLD patients (Lazaridis and Tsochatzis 2017). However, no other drugs have been approved for the treatment of NAFLD by the Food and Drug Administration (FDA) in the USA. The results of various therapeutic approaches using pioglitazone and metformin have recently been summarized (Le and Loomba 2012). Metformin has been suggested to inhibit mitochondrial complex activity and subsequently activate AMPK (Hinke et al. 2007). Metformin was found to be efficient in decreasing the serum levels of ALT in patient with NAFLD who were not diabetic (Le and Loomba 2012). Similarly, pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, was effective in ameliorating NASH in non-diabetic patients with NAFLD (Promrat et al. 2004). However, in addition to these beneficial effects, pioglitazone has side effects, such as osteopenia, fluid retention, and weight gain (Issa et al. 2017). Thus, it is generally recommended to lose weight through a modification of lifestyle and diet (Mishra and Younossi 2007).

Therapeutic approaches using antioxidants have also been implemented to protect against oxidative stress-induced liver injury. Among them, vitamin E has been widely used to treat patients with NAFLD (Ji et al. 2014). Indeed, vitamin E can effectively alleviate the liver injury and histological features in patients with NASH (Sato et al. 2015). However, the beneficial effect of vitamin E in normalizing serum ALT level was not found in a meta-analysis. Additionally, vitamin E therapy was not found to be effective for the child patients with NAFLD (Lavine et al. 2011). Therefore, further studies aimed at examining long-term tolerance and efficacy of vitamin E in specific subsets of patients are required, for example patient with NASH or diabetes-associated cirrhosis (Musso et al. 2013). Accumulating evidence has also suggested that plant-derived antioxidants including resveratrol, epigallo-catechin gallate, curcumin, coumestrol, silybin, anthocyanidins, and allyl-isothiocyanate can all improve the severity of NAFLD by increasing mitochondrial function. However, the selective permeability of the inner mitochondrial membrane (IMM) remains the major obstacle to mitochondria-targeted treatments. Several drugs have been used to deliver antioxidants to mitochondria. For instance, MitoQ, a lipophilic triphenylphosphonium (TPP) cation, can induce negatively charged hydrophobic IMM. Therefore, MitoQ may remain and act as an effective antioxidants with the IMM effectively (Smith et al. 2003; Asin-Cayuela et al. 2004; Rokitskaya et al. 2008). Indeed, MitoQ treatment has been shown to effectively improve cardiolipin-mediated mitochondrial integrity and metabolic syndrome features, and to induce antiapoptotic effects through the inhibition of caspase-3 activation and cytochrome c release (Dhanasekaran et al. 2004; Feillet-Coudray et al. 2014; Fouret et al. 2015). Similarly, a mitochondria-targeted vitamin E has been shown to be an effective agent in preventing peroxide-mediated transferrin-iron transport to mitochondria and eventually protecting against apoptosis (Dhanasekaran et al. 2005). Unfortunately, very few clinical trials have been conducted using these agents (Table 3).

Table 3 Mitochondria-related pharmacological agents in active phase 2 or 3 studies for treatment of NAFLD/NASH
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Encouragingly, several phase 3 clinical trials of other mitochondria-related drugs have been initiated to assess their therapeutic efficacy in patient with NAFLD (Konerman et al. 2018; Cai et al. 2019) (Fig. 3). Elafibranor is a dual peroxisome proliferation-activated receptor (PPAR)-α/δ agonist and has multiple protective effects in the pathogenesis of NAFLD (Staels et al. 2013). As mentioned previously, PPAR-α has been shown in several studies in humans and animals to attenuate triglyceride and FFAs accumulation, and the resulting hepatic inflammation (Tailleux et al. 2012; Staels et al. 2013). PPAR-δ can also decreases fatty acid uptake and regulate energy metabolism, including glucose and hepatic inflammation. Furthermore, PPAR-δ can improve insulin sensitivity by regulating lipid metabolism in adipose tissue (Riserus et al. 2008; Poulsen et al. 2012). Currently, one phase III trial of elafibranor is being conducted to evaluate the efficacy and safety in patients with NASH (Konerman et al. 2018). Apoptosis signal-regulating kinase 1 (ASK1) has been demonstrated to be a major player in the pathogenesis of oxidative stress-mediated hepatic injury, inflammation, and fibrosis. Its inhibitor, selonsertib, is also being explored in patient with NASH. There are currently two phase III trials of selonsertib, investigating its efficacy in patients with compensated cirrhosis and bridging fibrosis (F3) due to NASH (Konerman et al. 2018).

Fig. 3
figure 3

Mechanism of action of therapeutic targets for the treatment of NAFLD. As shown in previous figures, mitochondrial dysfunction has strong correlation with NAFLD. Along with many efforts to develop treatment for NAFLD, several mitochondria-targeting drugs are on the clinical trial. Elafibranor, dual peroxisome proliferation-activated receptor (PPAR)-α/δ agonist, is one of the drugs. As it is well known for PPAR-α agonist, it would attenuate hepatic inflammation associated with lipid metabolism and mitochondrial dysfunction. Next, selonsertib is an apoptosis signal-regulating kinase 1 (ASK1) inhibitor. This drug would inhibit mitochondrial malfunction in regards of apoptotic signaling from hepatocyte, which would activate kupffer cell. Aside from those two drugs, cenicriviroc is an antifibrogenic agent that target dual inflammatory receptor CCR2/CCR5. This drug would ameliorate progression of steatohepatitis to fibrogenesis targeting hepatic stellate cell. ASK Apoptosis signal-regulating kinase, CB1 cannabinoid receptor type, CCR C–C chemokine receptor, ER endoplasmic reticulum, FGF fibroblast growth factor, FFA free fatty acids, FXR farnesoid X receptor, GLP-1 glucagon-like peptide-1, PPAR peroxisome proliferator-activated receptor, ROS reactive oxygen species, SHP small heterodimer partner, SREBP sterol regulatory element binding protein

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Conclusion

The pathogenesis of NAFLD involves metabolic dysregulation, inflammation and fibrosis. Numerous clinical trials have been conducted targeting each of these components. Currently, it is well accepted that a combination therapeutic strategy should be adopted with a backbone treatment and a complementary treatment for patients with NAFLD. Backbone treatment generally includes metabolic modulation, while complementary treatment targets the modulation of inflammation or fibrosis. Of note, mitochondrial processes are involved in both modulations in therapeutic targets for NAFLD. Mitochondria regulate ROS formation, oxidative stress, and lipid metabolism in the early stage of simple steatosis. Over time, the increased injury to hepatocytes produce various DAMPs, which in turn promote steatohepatitis and fibrosis. Thus, maintaining mitochondrial integrity by mitophagy may be a key factor for protecting against treating NAFLD. Furthermore, preclinical and clinical research addressing therapeutic approaches that target mitochondrial process will be required in the near future.