Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 May;76(9):1641-1652.
doi: 10.1007/s00018-018-2990-x. Epub 2018 Dec 11.

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  4
Affiliations
Review

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

Prakash P Praharaj et al. Cell Mol Life Sci. 2019 May.

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: Cancer therapy; Cardiolipin; Ceramide; Mitochondrial apoptosis; Mitophagy; Sphingosine-1-phosphate.

PubMed Disclaimer

Conflict of interest statement

The authors disclose no conflict of interest.

Figures

Fig. 1
Fig. 1
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
Fig. 2
Fig. 2
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
Fig. 3
Fig. 3
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
Fig. 4
Fig. 4
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
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005;6:389–402. doi: 10.1038/nrg1606. - DOI - PMC - PubMed
    1. Kang D, Hamasaki N. Alterations of mitochondrial DNA in common diseases and disease states: aging, neurodegeneration, heart failure, diabetes, and cancer. Curr Med Chem. 2005;12:429–441. doi: 10.2174/0929867053363081. - DOI - PubMed
    1. Horvath SE, Daum G. Lipids of mitochondria. Prog Lipid Res. 2013;52:590–614. doi: 10.1016/j.plipres.2013.07.002. - DOI - PubMed
    1. van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008;9:112–124. doi: 10.1038/nrm2330. - DOI - PMC - PubMed
    1. Vance JE. Phospholipid synthesis and transport in mammalian cells. Traffic (Cph, Den) 2015;16:1–18. doi: 10.1111/tra.12230. - DOI - PubMed

LinkOut - more resources

  NODES
twitter 2