Lipid-mediated signals that regulate mitochondrial biology

Abstract

For decades, lipids were assumed to fulfill roles only in energy storage and membrane structure. Recent studies have discovered critical roles for phospholipids, sphingolipids, and sterols in many cellular pathways, including cell signaling and transcriptional regulation. Frequently, lipids from these various classes work together to achieve defined cellular outcomes. Specific mitochondrial lipids are critical for proper assembly of the electron transport chain complexes and for effective responses to mitochondrial damage, including maintenance of mitochondrial protein homeostasis, regulation of mitophagy, and induction of apoptosis. In this Minireview, we will primarily focus on mitochondrial lipid signaling mediated by lipid-protein interactions.

Keywords: cell signaling; lipid peroxidation; lipid signaling; lipid–protein interaction; mitochondria; mitophagy; proteostasis; sphingolipid; sterol; stress response.

Figure 1.

Mitochondrial lipids contribute to several mitochondrial functions. A, under mitochondrial stress conditions, ergosterol (erg) oxidation to ergosterol peroxide (EP) recruits the Vms1–Cdc48 complex to mitochondria to aid in maintaining mitochondrial protein homeostasis. B, in response to mitochondrial damage, cardiolipin (CL) translocates from the mitochondrial inner membrane to the outer membrane where cardiolipin and ceramide (Cer) bind LC3 and LC3B-II to recruit autophagosomes to damaged organelles. C, mitochondrial damage can also lead to accumulation of mitochondrial ceramide where BAX and ceramide work synergistically to create proteolipid pores through which cytochrome c can exit and activate the apoptotic pathway. D, sphingosine 1-phosphate (S1P) binds the chaperone prohibitin (PHB2), which facilitates PHB2 interactions with cytochrome c oxidase and its subsequent assembly.