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. 2018 Dec 11;76(9):1641–1652. doi: 10.1007/s00018-018-2990-x

Intricate role of mitochondrial lipid in mitophagy and mitochondrial apoptosis: its implication in cancer therapeutics

Prakash P Praharaj 1, Prajna P Naik 1,2, Debasna P Panigrahi 1, Chandra S Bhol 1, Kewal K Mahapatra 1, Srimanta Patra 1, Gautam Sethi 3, Sujit Kumar Bhutia 1,✉
PMCID: PMC11105358  PMID: 30539200

Abstract

The efficacy of chemotherapy is mostly restricted by the drug resistance developed during the course of cancer treatment. Mitophagy, as a pro-survival mechanism, crucially maintains mitochondrial homeostasis and it is one of the mechanisms that cancer cells adopt for their progression. On the other hand, mitochondrial apoptosis, a precisely regulated form of cell death, acts as a tumor-suppressive mechanism by _targeting cancer cells. Mitochondrial lipids, such as cardiolipin, ceramide, and sphingosine-1-phosphate, act as a mitophageal signal for the clearance of damaged mitochondria by interacting with mitophagic machinery as well as activate mitochondrial apoptosis via the release of cytochrome c into the cytoplasm. In the recent time, the lipid-mediated lethal mitophagy has also been used as an alternative approach to abolish the survival role of lipid in cancer. Therefore, by _targeting mitochondrial lipids in cancer cells, the detailed mechanism linked to drug resistance can be unraveled. In this review, we precisely discuss the current knowledge about the multifaceted role of mitochondrial lipid in regulating mitophagy and mitochondrial apoptosis and its application in effective cancer therapy.

Keywords: Cardiolipin, Ceramide, Sphingosine-1-phosphate, Mitophagy, Mitochondrial apoptosis, Cancer therapy

Introduction

Mitochondria are essential organelles for cell proliferation and metabolic processes, and act as a central player in the mitophagy and mitochondrial apoptosis. A defect in mitochondrial functions leads to severe health disorders such as cancer, neuro-degeneration diseases, and other age-related disorders [1, 2]. Mitochondrial membranes are mainly composed of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), cardiolipin (CL), and phosphatidylserine (PS) (given in the decreasing order of their abundance) [3–5]. Among these, CL and PE are mainly synthesized by the mitochondria, whereas for other phospholipids, mitochondria depend on endoplasmic reticulum (ER) [5]. Since several decades, lipids have been believed to be only a part of membrane structure and an alternative energy source. However, current findings have revealed their involvement (e.g., phospholipids, sterols, and sphingolipids) in several cellular signaling cascades leading to the achievement of desired cellular outcomes [6].

In mitophagy, which is a selective form of autophagy, the entire dysfunctional mitochondria with inefficient oxidative phosphorylation are enclosed in a double-membranous vesicle called mitophagosome and are _targeted for lysosomal degradation [7, 8]. In 2005 for the first time, John Lemasters used the term ‘mitophagy’, since then the majority of research is focusing on identifying its different components. In 2008, Richard Youle and his groups reported that the elimination of damaged mitochondria is mediated through the complex interplay between the E3 ubiquitin ligase Parkin and the Ser/Thr kinase PINK1 (PTEN-induced putative kinase 1) [9]. In healthy mitochondria, PINK1 is imported to mitochondria, followed by its proteasomal degradation via mitochondria intermembrane space protease called as PARL, which cleaves its mitochondrial _targeting sequence [10–12]. A mitochondrial damage causes PINK1 accumulation in the MOM, with subsequent phosphorylation of Parkin and ubiquitin at Ser65 [13, 14]. Being selective autophagy, mitophagy requires all autophagic proteins necessary for autophagosome formation [15], mitochondrial fission (such as Drp1, fis1, and mfn), ubiquitin adaptors (such as NDP52, p62/SQSTRM1, NBR1, TAX1BP1, and Optineurin) [16] and several mitophagy receptors (such as NIX/BNIP3L [17], BNIP3 [18], FUNDC1 [19], AMBRA1 [20], and Bcl2-L13 [21]). These proteins directly and/or indirectly interacts with LC3 via its LIR motif Y (18) xxL promoting mitophagy (see Fig. 1). When mitophagy degrades mitochondria before activating caspase-dependent apoptosis, mitophagy behaves as a cell survival mechanism. Conversely, excessive mitophagy leads to the release of lysosomal enzymes (i.e., cathepsins) to stimulate caspase-dependent apoptosis [22].

Fig. 1.

Fig. 1

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Mechanistic detail of mitophagy. Under different stress, proteins present on the MOM such as Bcl2-L13, NIX, BNIP3, FUNDC1, and AMBRA1 act as mitophagic receptor and interact directly with LC3 to remove superfluous mitochondria, a process categorized as receptor-mediated mitophagy. On the contrary, NDP52, TAX1BP1, NBR1, p62/SQSTM, and OPTN act as mitophagic adaptor and interact simultaneously with ubiquitin and LC3-promoting ubiquitin-mediated mitophagy

Mitochondrial apoptosis is a precisely regulated form of cell death, where cells undergo drastic changes (i.e., shrinkage, chromatin condensation, and nuclear fragmentation) with subsequent removal in the form of apoptotic bodies by phagocytosis [23]. During this process, the proteins [e.g., cytochrome c (cyt c) and other pro-apoptotic factors] that act normally in the intermembrane space of mitochondria pass into the cytosol depending on mitochondrial damage and subsequent permeabilization of mitochondrial outer membrane (MOM) [24]. Once in the cytosol, cyt c binds to the adaptor molecule APAF-1, which undergoes extensive conformational changes and oligomerizes to form apoptosome (a heptameric structure) followed by recruitment and activation of a cascade of caspases (cysteine aspartyl-specific proteases) (such as caspase-9, caspase-3, -6, -7); this eventually leads to the cell death [25, 26]. In another way, if caspases are not activated, the mitochondrial outer membrane permeabilization (MOMP) also leads to cell death [27]. As mitochondria maintain the balance between tumorigenesis and cell death, the major focus of cancer research is _targeting mitochondria (more specifically mitochondrial lipid) for an effective anti-cancer therapy. In this review, we focus on the status of our current understanding on the involvement of mitochondrial lipids in mitochondrial function, homeostasis with a specific focus on mitophagy and mitochondrial apoptosis, and its therapeutic applications in cancer.

Multifaceted role of mitochondrial lipids in regulating mitophagy

The subcellular distribution of individual lipids has a significant impact on the lipid–protein interactions, modulating the cellular functionality and activity of _target proteins or by directing proteins to different regions of the cell for organelle-specific activities.

Cardiolipin: role in clearing dysfunctional mitochondria

In eukaryotes, CL is a specialized non-bilayer forming phospholipid synthesized by the action of CL synthase (CRD1), which condenses PG and CDP-diacylglycerol (CDP-DAG) [28, 29]. In healthy mitochondria, CL is involved in lipid–protein interactions, necessary for mitochondrial function including, mitochondrial cristae formation, better assembly, and functioning of electron transport chain complexes as well as membrane fusion [30–33]. Any damage to mitochondria or depolarization of its membrane results in the translocation of CL to MOM, which is an initiator signal for mitophagy [34–36]. In 2013, Chu et al. [34] established the functional relationship between CL translocation from mitochondrial inner membrane (MIM) to MOM and mitophagy. Through direct liposome-binding assays, site-directed mutagenesis and computational modeling, microtubule-associated-protein-1 light-chain-3 (LC3) was found to bind with CL. Inhibiting this molecular interaction prevents rotenone-induced mitochondrial delivery to autophagic machinery and reduces mitochondrial loss [37]. LC3 has a putative CL binding site at its N-terminal α-helices necessary for the direct interaction between MOM and mitophagosome culminating into mitophagy but not important for non-selective form of autophagy [34, 37]. When cells were exposed to carbonyl cyanide m-chlorophenyl hydrazine (CCCP) (membrane depolarizer) and rotenone (a complex I inhibitor and mitophagy inducer), a high percentage of CL was observed on the MOM [34]. This translocation of CL is tightly regulated by phospholipid scramblase-3 (PLS3) [34] or nucleoside diphosphate kinase D (NDPK-D) [35]. PLS3 maintains the balanced distribution of CL between outer and inner membrane leaflets, [34] whereas NDPK-D a hexameric intermembrane space protein acts as a CL-translocating machinery, which assists in CL redistribution to the MOM [35]. Additionally, in situ proximity ligation assay (PLA) confirmed the CL-transfer activity of NDPK-D, in close association with OPA1, a dynamin-like GTPase-linking mitochondrial fission–fusion cycle with mitophagy [35]. Therefore, CL redistribution acts as an “eat-me” signal for the removal of dysfunctional mitochondria (see Fig. 2).

Fig. 2.

Fig. 2

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Multifunctional role of cardiolipin in regulating mitophagy and mitochondrial apoptosis. During mitophagy, cardiolipin translocates from MIM to MOM by the action of NDPK-D, followed by interaction with LC3A for the clearance of dysfunctional mitochondria. Whereas, in mitochondrial apoptosis cardiolipin oxidized by the peroxidase activity, cyt c results in its translocation to the MOM where tBID–CL interaction induces the Bax/Bak oligomerization initiating the mitochondrial disruption and release of cyt c to initiates apoptosis

The changes in CL species, specifically a decline in tetralinoleoyl CL (the most abundant CL in highly active metabolic tissues), interrupt mitophagy [34, 38], causing the accumulation of fragmented and/or dysfunctional mitochondria. Hsu et al. [38] reported the functional involvement of Tafazzin (TAZ)—a known CL remodeling transacylase—in regulating mitochondrial function and mitophagy without affecting autophagosome biogenesis. The molecular interaction between LC3B and CL is more specific than other di-anionic lipids [e.g., phosphatidylinositol-4-phosphate (PtdIns4P)] with positive cooperativity. Moreover, it depends on both electrostatic forces and CL-specific changes in the membrane properties where the C terminal end of LC3B remains open toward the hydrophilic environment after binding with CL-enriched membranes [39]. Shen et al. [40] have reported that CL controls the mitophageal degradation via protein kinase C pathway. Recently, Shimasaki et al. [41] observed that CL plays a major role in the translocation of p210 BCR-ABL [most common variant causing chronic myeloid leukemia (CML)] from cytosol to mitochondria to manage mitochondrial damage. The Pleckstrin homology (PH) domain of p210 BCR-ABL efficiently recognizes CL, via its Arg726 residue present in the ligand-binding region essential for this lipid–protein interaction [41]. This study unraveled the importance of CL, PH domain, and p210 BCR-ABL in CML pathogenesis. By looking at these studies, the importance of CL translocation, an indicator of mitochondrial dysfunction in mitophagy and cancer progression, could be ascertained.

Ceramide: a critical regulator of mitophagy

Numerous studies in the recent times suggest that ceramide could act locally in mitochondria and get involved in the regulation of mitophagy (see Fig. 3). When cells are exposed to various cell stressors, the activity of ceramide synthase (CerS) inside the cells goes high with subsequent accumulation of ceramide in the cell that leads to cell death [42, 43]. Obeid and his group reported a novel pathway involved in the production of ceramide in the intact liver mitochondria. Two mitochondrial enzymes, viz., mitochondrial thioesterase and neutral ceramidase (NCDase) regulate this pathway. First, thioesterase hydrolyzes palmitoyl-CoA to palmitate and CoA, and then NCDase forms ceramide by condensing palmitate with sphingosine in a reverse ceramidase reaction inside the mitochondria [44]. In another study, Novgorodov et al. identified two isoforms of CerS (i.e., CerS6 and CerS2) in isolated rat brain mitochondria. CerS6 is present in MIM in association with adenine nucleotide translocase and CerS2 is abundant in MOM along with Tom20 [45]. In 2012, Sentelle et al. [46] reported a mechanistic connection between ceramide signaling and mitophagy while exploring the autophagy inducing potential of C18-ceramide. In this study, they found that C18-ceramide selectively _targets mitochondria to LC3B-II containing autophagolysosomes. After C-18 treatment, LC3B-phosphatidylethanolamine gets lipidated to form LC3B-II, which then binds to ceramide on the MOM suggesting that ceramide–LC3B-II interaction is the key factor leading to lethal mitophagy [46].

Fig. 3.

Fig. 3

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Role of ceramide in controlling mitophagy and mitochondrial apoptosis. During mitophagy, ceramide translocates to MOM where it interacts with ceramide-binding domain of LC3II for the removal of damaged mitochondria. On the other hand, in mitochondrial apoptosis ceramides form stable pores known as ceramide channel in the phospholipid bilayer. Along with activated BAX, it makes the release of cytochrome c from the mitochondria to activate apoptosis

In 2016, Ogretmen and his group reported that CerS1/C18-ceramide selectively induces lethal mitophagy in FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-mediated acute myeloid leukemia (AML) [47]. The inhibition of FLT3-ITD signaling (both at molecular and pharmacological level) activates Drp1 and generates CerS1/C18-ceramide by the mitochondrial CerS1. Further, the mitochondrial C18-ceramide interacts with LC3B-II via I35/F52 residues present in its ceramide-binding domain, in order to recruit autophagosomes to mitochondria to initiate mitophagy-dependent cell death [47]. Recently, we reported that PUMA, a BH3-only pro-apoptotic Bcl2 family protein, is responsible for inducing lethal mitophagy in glioblastoma cells [48]. Upon ceramide stress, ceramide synthase-1 activation leads to ER stress and the accumulation of ROS, which triggers mitochondrial damage. In this condition, PUMA interacts with LC3 via its C-terminally located LC3 interacting region (LIR) and leads to lethal mitophagy [48].

Sphingosine-1-phosphate and mitophagy

Sphingosine-1-phosphate (S1P) is one of the most widely studied bioactive sphingolipids [49] produced intracellularly by two closely related sphingosine kinases: SphK1 and SphK2. Mitochondrial S1P is mostly generated from sphingosine by the action of SphK2 [50]. SphK2 enhances autophagy level by directly interacting with Bcl-2 via a putative BH3 domain to displace Beclin-1 independent of its catalytic activity [51]. S1P is directly involved in the LC3 lipidation after a cleavage mediated by the action of Sphingosine-1-phosphate lyase 1 (SGPL1) to form hexadecenal and ethanolamine phosphates, which can be directed to the synthesis of PE. S1P directly interacts with prohibitin2 (PHB2), which is a highly conserved chaperone that regulates mitochondrial assembly and function [50] and a receptor protein for mitophagy [52]. Mitroi et al. [53] reported that the depletion of SGPL1 reduces PE levels and impairs LC3 lipidation causing an accumulation of phagophore-like structures and autophagic substrates, including p62 and aggregate-prone proteins. The addition of PE to SGPL1-deficient cells restores LC3-II levels and autophagic flux suggesting that S1P regulates PE availability for LC3 lipidation and the elongation of phagophores [53].

Mitochondrial lipid: the dynamic regulator of mitochondrial apoptosis

Mitochondrial lipids act as a stress sensor in cancer cells, which not only regulate the shape, structure, and function of mitochondria but also are involved in the regulation and propagation of mitochondrial apoptosis. In this section, we describe the functional role of different mitochondrial lipids with respect to mitochondrial apoptosis.

Cardiolipin (CL): mitochondrial localization, molecular interaction under apoptotic stimuli

In healthy cells, CL interacts with all the proteins present in the MIM (such as the electron transport chain complexes I, III, IV, V and cyt c) and because of the presence of a small head group with four fatty acyl chains, it serves as a proton sink in the proximity of energy transducing macromolecules [54]. Free and loosely bound cyt c (about 85% of the total cyt c) contributes to the transfer of electrons, inhibiting ROS formation in preventing oxidative stress. Conversely, the tightly bound cyt c (15%) confers peroxidase activity, a crucial event for initiating apoptosis [55]. Under ‘normal’ conditions when cyt c carrying electrons, the functional positions in its haeme iron are occupied and it undergoes conformational change when bound to CL and it becomes partially unfolded [56]. During mitochondrial apoptosis, cyt c drives the oxidation of protein and lipid substrates (preferably CL) leading to the accumulation of CL-hydroperoxides and translocation of both cyt c and CL-hydroperoxide species to the MOM [56]. The formation of highly oxidized heme in the CL/cyt c complex in the presence of hydrogen peroxide (H2O2) implies the subtraction of one electron from unsaturated acyl chains of CL and formation of a lipid hydroperoxide. In the absence of H2O2, this lipid hydroperoxide acts as an alternative substrate for the peroxidase activity of cyt c, which is required for lipid peroxidation [57].

CL is mostly located at the contact region between MOM and MIM and acts as the _target site for tBID, a protein appointed for the apoptotic message transmission [58]. tBID first alters the structure of the mitochondrion by binding to CL via its alphaH6 helix; successively, in cooperation with CL, it induces the Bax/Bak oligomerization (a process requiring the BH3 domain of tBID), which initiates the mitochondrial disruption [59]. The tBID–CL interaction also plays a critical role in the cristae-remodeling essential for the release of cyt c into the cytosol and for the formation of fission sites in the mitochondrion [60]. The release of cyt c is attributed to the formation of the mitochondrial apoptosis-induced channel (MAC, formed by Bak and/or Bax) in the outer mitochondrial membrane followed by activation of caspase 9, via cyt c to initiates apoptosis [61]. In a recent study, Lai et al. [62] have reported that BAX undergoes dimerization to form active oligomers (lethal oligomer) in the presence of CL. The active oligomers form a stable pore in the membrane that leads to MOMP [62] (see Fig. 2).

Ceramide: a bona fide transducer in mitochondrial apoptosis

Mitochondrial ceramide is produced inside cells in response to various stress (pro-apoptotic) stimuli, such as IR, CD95/Fas, and TNF-α cell via sphingomyelin hydrolysis or de novo synthesis [63, 64]. Birbes et al. [65] reported that MCF-7 cells possess a set of mitochondria-specific ceramide (not present in any other organelle), responsible for the induction of apoptosis. The addition of exogenous ceramides to mitochondria or to cultured cells induces the release of cytochrome c from mitochondria, which is the initiator signal for mitochondrial apoptosis [65]. Ceramide activates serine/threonine protein phosphatases (e.g., PP1 and PP2A), which are the important intracellular effector molecules of apoptosis [42]. PP1 is responsible for the dephosphorylation of pRB (retinoblastoma susceptibility gene) that leads to cell cycle arrest at the G1 phase in the presence of ceramide [66].

Ceramide and activated BAX together are responsible to form stable pores known as ceramide channel in the phospholipid bilayer that makes the release of cytochrome c from the mitochondria to activate apoptosis [67]. The formation and stability of ceramide channel are mostly affected by the ceramide concentration, frequency of their synthesis, and breakdown [68], and their transport for the mitochondrial _targeting of the ceramide transfer protein (CERT), which is involved in their import into mitochondria [69]. Bcl-2 overexpression leads to the accumulation of ceramide due to the reduction of nSmase1 activation followed by subsequent apoptosis in glioma cells [70]. Yabu et al. [71] showed that when neutral sphingomyelinase1 (nSmase1) or bacterial sphingomyelinase was _targeted to mitochondria, apoptosis was induced by promoting the hydrolysis of sphingomyelin that was finally converted into ceramide. The addition of Bcl-xL to rat mitochondria prevented ceramide-induced MOMP by disassembling ceramide channels in the phospholipid membranes that inhibited the release of cytochrome c [72].

The ceramide-enriched membrane is the primary requirement for BAX oligomerization [73] and its translocation is facilitated by activating p38 MAPK or downregulating AKT [74]. Ceramide arbitrates MOMP by activating glycogen synthase kinase 3β (GSK3β) through PP2A and activates cathepsin D, which then activates a series of caspases including caspase-2 and caspase-8, and finally leads to the cleavage of a BID to form tBID [66]. Activation of BAK is essential and enough to drive the activity of ceramide synthase (CerS) via a feed-forward mechanism that leads to the accumulation of ceramide inside the cell following inhibition of BCL2-like proteins leading to the formation of the ceramide channel [75] (see Fig. 3).

Sphingosine-1-phosphate (S1P) and its role in mitochondrial apoptosis

In addition to ceramide, sphingosine also regulates mitochondrial apoptosis in a ceramide-independent pathway. When human neutrophils were exposed to TNF-α, a higher production of sphingosine and ceramide inside the cells leads to apoptosis. However, when sphingosine was supplemented alone exogenously, the effect of TNF-α was recapitulated suggesting that the sphingosine-deacetylated product of ceramide controls induction of TNF-α [76]. Sphingosine-induced apoptosis was found to be caspase dependent and started earlier than ceramide-mediated apoptosis, which signifies that apoptosis induction is solely because of sphingosine and not because of its conversion to ceramide [77].

Under different stress, S1P is degraded by S1P lyase to form hexadecenal, which then binds to the apoptosis regulator BAX, promoting its oligomerization followed by the release of cytochrome c [78]. The BH3 domain of SphK2 favors its binding with pro-apoptotic BCL-XL, which abolishes its anti-apoptotic effect [79]. Chipuk et al. [78] have shown, using purified mitochondria, that sphingolipid metabolism works together with BAK and BAX activation leading to the release of cytochrome c in coordination with BH3-only proteins and a specific lipid environment followed by MOMP sensitization promoting the mitochondrial apoptosis. The overexpression of SphK/S1P signaling develops resistance to chemotherapy, radiation therapy, and hormonal therapy in various types of cancers, including breast, prostate, and pancreatic cancers [49, 80]. Whereas, knocking down SphK2 with siRNA or inhibiting its activity with the selective pharmacological drugs reduces cancer cell growth, migration, and invasion [81, 82].

Mitochondrial lipid: a potential _targets for anti-cancer therapy

Even though chemotherapy is one of the most widely adopted approaches for effective cancer treatment, its efficacy is restricted because of drug resistance developed due to drug _target alterations, pro-survival pathway activation, and ineffective cell death induction [83]. Currently, many attempts are being made to develop drugs, which specifically inactivate the pro-survival pathway or stimulate cell death pathway (mitochondrial apoptosis) so that the tumor cells are removed. This could be an ideal strategy for anti-cancer therapy.

How can the survival role of mitochondrial lipid be _targeted for cancer cell death?

Mitochondrial lipid-induced mitophagy is context dependent and acts either as a cell survival or as a death mechanism in cancer cells. For cell survival, it eliminates the mitochondria which are getting ready to initiate caspase-dependent apoptosis [84]. However, when excessive removal of mitochondria without proper biogenesis or metabolic balance occurs for longer duration, it leads to lethal mitophagy and cell death [85]. For example, C18-ceramide was accumulated in the MOM to interact with LC3B-II recruiting autophagic machinery to trigger lethal mitophagy and tumor suppression in head and neck squamous cell carcinoma (HNSCC) in a non-apoptotic manner, independent of caspase and Bax/Bak activity. Mitochondrial depolarization, decreased ATP generation, and DRP-1 oligomerization accompanied this process [46, 85]. Dany et al. [47] reported that LCL-461 which is an analog drug for mitochondria-_targeted C18-ceramide is effective against crenolanib resistance by inducing lethal mitophagy in FLT3 mutated AML cells, in NSG mice with crenolanib-resistant AML xenografts, and in human FLT3-ITD1 AML blasts, whereas the known inhibitors of FLT3-ITD, such as quizartinib (AC220), sorafenib, and crenolanib, showed a high therapeutic efficacy in preclinical models but failed to produce desirable results in clinical trials due to the resistance developed against the drugs [86]. In another study, Thomas et al. [87] reported that triggering ceramide signaling in human papillomavirus (HPV)-associated HNSCC leads to lethal mitophagy in cancer cells resulting in tumor suppression. Moreover, using different pharmacological, and genetic approaches, they showed that HPV early protein 7 (E7) increases the level of ceramide-mediated lethal mitophagy by selectively inhibiting retinoblastoma protein (RB), which releases E2F5. E2F5 then associates with DRP1, providing a supportive platform for the activation of Drp1 and its mitochondrial translocation, resulting in mitochondrial fission mediating high level of lethal mitophagy-driven tumor suppression [87]. Thus, _targeting mitophagy might affect the equilibrium between cancer progression and cell death (see Fig. 4).

Fig. 4.

Fig. 4

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Mitochondrial lipid in _targeting cancer cells for better anti-cancer therapy. Mitochondrial lipids could be useful for _targeted removal of cancer cells by either inhibiting various enzymes necessary for S1P and cardiolipin-mediated protective mitophagy or activating ceramide production or exogenous supplying of LCL-461 to induce lethal mitophagy and apoptosis in cancer cells

In another mechanism, cancer cells develop therapeutic resistance by upregulating SphK/S1P signaling, which leads to a higher production of S1P, a tumor-promoting lipid. In the recent time, multiple lines of experiments show that the inhibition of SphK2 at both pharmaceuticals as well as at the genetic level can rule out MDR-associated chemo-resistance in different cancer types [88, 89]. A breast cancer cell line, MCF-7, shows enhanced sensitivity toward doxorubicin by the loss of function of SphK2 [90]. Sorafenib (BAY 43-9006), one of the clinically approved drugs against renal cell carcinoma [91], is also used against melanoma and breast cancer in combination with nanoliposomal ceramide for effective treatment [92]. The selective inhibition of SphK2 by the pharmacological inhibitors such as ABC294640 and K145 has shown anti-cancer effects [89]. Furthermore, a phase I clinical study on ABC294640 in patients with advanced solid tumors reported a partial response in a patient with cholangiocarcinoma with various solid tumors, suggesting that SphK2 is an attractive therapeutic _target [93]. In addition, a combination of sorafenib and an inhibitor of either SphK1/2 or SphK2 can inhibit the growth of kidney carcinoma and human pancreatic adenocarcinoma cells under in vitro as well as in vivo condition [94]. However, more studies are needed to be performed _targeting various mitochondrial lipids or specific enzymes required for their biosynthesis to abolish the survival role of mitochondrial lipid that would be beneficial for effective cancer treatments.

Which switch should be on to activate cancer cell death?

Mitochondrial lipids are widely believed to be a master regulator of apoptosis but how these molecules specifically _target cancer cells and commit to death is not well known. Ceramide as a tumor-suppressive lipid acts as a crucial factor in modulating cancer progression. Ceramide-induced apoptosis can be enhanced by _targeting enzymes involved in ceramide biosynthesis pathway (see Fig. 4). Gain of function of CerS1 increased the sensitivity of HEK293T cells toward different anti-cancer drugs including carboplatin, doxorubicin, vincristine, and cisplatin, while CerS5 overexpression augmented its sensitivity toward vincristine and doxorubicin [95]. In prostate cancer cells, the addition of DM102 (an acid ceramidase inhibitor) enhances cytotoxic effects of fenretinide [96], whereas, in case of breast cancer cell lines, exogenous addition of C6 ceramide showed similar effects [97]. Tamoxifen increases the cytotoxicity of C6 ceramide in breast cancer cells, by arresting the cell cycle and causing high MOMP that leads to caspase-dependent apoptosis [98]. Downregulation of Protein Tyrosine Phosphatase localized to the Mitochondrion 1 (PTPMT1), an MIM protein with a phosphatase domain exposed to the matrix, sensitizes cancer cells towards currently available chemotherapeutics through induction of apoptosis [99].

During the course of treatment, cancer cells develop resistance towards drugs by overexpressing anti-apoptotic proteins (Bcl-2 and Bcl-xL), which prevent the permeabilization of MOM and thus the release of cyt c into the cytoplasm [100]. Therefore, intracellular delivery of cyt c from outside of the cell is one way to initiate apoptosis in cancer cells by evading the anti-apoptotic factors preventing the release of the “own” cyt c from the cell mitochondria. However, cyt c is impermeable to the cellular membrane. In the recent time, several different nano-sized cyt c delivery systems have been developed to address these issues [101–103]. In 2012, Kim et al. developed a lipoprotein-based delivery platform using refined lipid bilayers of DOTAP/DOPE lipids and apo-lipoprotein for transporting MPS-conjugated cyt c. This nanocarrier-mediated platform specifically delivers cyt c into cancer cells (both into non-small cell lung carcinoma cells and tumor tissue) to induce apoptosis and tumor growth retardation in vivo [101]. In another study, Mendez et al. [102] designed a mesoporous silica nanoparticle system for the _targeted delivery of immobilized chemically glycosylated cyt c into HeLa cells to induce apoptosis. The major drawback of these systems is that all cyt c carriers are formulated using synthetic compounds (i.e., mimicking a natural event through non-naturally occurring compounds). Then, in 2017, Vladimirov et al. [103] designed a biomaterial-based anti-cancer nano-formulation having cyt c and CL, which directly acts upon the cell membrane and/or mitochondrial membranes leading to lipid peroxidation. In this study, they examined the cytotoxic and pro-apoptotic effect of this cyt-CL complex in both drug-sensitive and -resistant cancer cells. Moreover, they studied the mechanism by which free radicals are formed by the cyt-CL complex using tetraoleoyl CL (cardiolipin resistant toward lipid peroxidation) to mediate pro-apoptotic effects [103]. It can be inferred through these findings that a combination of mitophagy inhibitors and classical chemotherapeutics can improve the effectiveness of chemotherapy.

Conclusion and future prospective

Mitochondria, as a central player, maintain the balance between the cancer cell survival and mitochondria-mediated cancer cell death. Therefore, in this review, we have made an effort to summarize the present understanding about various mitochondrial lipids and their dynamic roles in both mitophagy and mitochondrial apoptosis in connection with more effective cancer therapy. Even though many developments have been made about mitochondrial lipids, several concerns remain such as how mitochondrial dynamics regulate the distribution and trafficking of individual lipids. Do mitochondrial lipids translocate to any specific organelle to carry selective autophagy? Is there any condition where an alteration in CL biosynthesis can lead to cancer development? What are the factors that decide whether sphingolipid-induced mitophagy is cytoprotective or lethal? Is it the length of fatty acyl chain or its intracellular location that decide the nature of mitophagy? Cancer cells mostly alter lipid metabolism to develop therapeutic resistance against different chemotherapeutic drugs. Therefore, by _targeting enzymes of lipid metabolism using specific inhibitors or a combination of different drugs along with inhibitors could offer a new promising approach for cancer therapy (Fig. 4). In addition, inhibiting the pro-survival pathway adopted by cancer cells and activating pro-death signaling cascade using specific pharmacological inhibitors or inducers would be an ideal strategy for cancer treatment. Gathering information about how cancer cells skip apoptosis via mitochondrial lipid-mediated signaling cascades and discovering more potent and safe inhibitors of mitochondrial lipids will provide opportunities for more practical and effective cancer therapy.

Acknowledgements

Research support was partly provided by Department of Biotechnology (Grant number BT/PR7791/BRB/10/1187/2013); Science and Technology Department, Government of Odisha; the Board of Research in Nuclear Sciences (BRNS) (number 37(1)/14/38/2016-BRNS/37276), Department of Atomic Energy (DAE); Science and Engineering Research Board (SERB) (number EMR/2016/001246), Department of Science and Technology.

Compliance with ethical standards

Conflict of interest

The authors disclose no conflict of interest.

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