Mechanisms by Which Dietary Fatty Acids Regulate Mitochondrial Structure-Function in Health and Disease

Abstract

Mitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a role in maintaining cellular homeostasis and proper calcium concentrations, building critical components of hormones and other signaling molecules, and controlling apoptosis. Structurally, mitochondria are unique because they have 2 membranes that allow for compartmentalization. The composition and molecular organization of these membranes are crucial to the maintenance and function of mitochondria. In this review, we first present a general overview of mitochondrial membrane biochemistry and biophysics followed by the role of different dietary saturated and unsaturated fatty acids in modulating mitochondrial membrane structure-function. We focus extensively on long-chain n-3 (ω-3) polyunsaturated fatty acids and their underlying mechanisms of action. Finally, we discuss implications of understanding molecular mechanisms by which dietary n-3 fatty acids target mitochondrial structure-function in metabolic diseases such as obesity, cardiac-ischemia reperfusion injury, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and select cancers.

FIGURE 1

Structure of mature cardiolipin. Cardiolipin is a unique anionic phospholipid with 4 acyl chains and a small headgroup. Mature cardiac cardiolipin contains predominantly 4 linoleic acid (18:2) acyl chains under healthy conditions. Modifications to the acyl chains of cardiolipin are common in a range of diseases and can also be modified in response to dietary intake of differing FAs.

FIGURE 2

Biosynthesis of mature CL. Mature CL is largely synthesized in the IMM. Nascent CL is synthesized from PG by using CDP-DAG. The acyl chains of nascent CL are then modified to mature CL containing 4 linoleic acid acyl chains (18:2) with the enzyme TAZ. Nascent CL can also undergo acyl chain cleavage with PLA2 to produce MLCL, which can serve as a substrate for MLCLAT1 to produce mature CL. A small fraction of mature CL is produced in the endoplasmic reticulum membrane through the use of ALCAT1. For simplicity, biosynthesis of other key phospholipids is not depicted. These phospholipids (PC, PE, PS, PI, PG, and PA) are found in differing concentrations across the ER, OMM, and IMM. ALCAT1, acyl-CoA:lysocardiolipin acyltransferase 1; CDP-DAG, cytidinediphosphate-diacylglycerol; CL, cardiolipin; CRLS1, cardiolipin synthase; ER, endoplasmic reticulum; IMM, inner mitochondrial membrane; MAM, mitochondria-associated membrane; MLCL, monolyso-cardiolipin; MLCLAT1, monolyso-cardiolipin acyltransferase 1; OMM, outer mitochondrial membrane; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PLA2, phospholipase A₂; PS, phosphatidylserine; TAZ, taffazin; (18:2)₄CL, tetralinoleoyl cardiolipin.

FIGURE 3

Model depicting how dietary SFA, n–6 PUFA, and n–3 PUFA acyl chains target IMM structure-function. An increase in n–3 PUFA acyl chains within the IMM will replace the n–6 PUFA acyl chains and thereby influence microviscosity. This may cause the membrane to become “leaky” and allow for more proton leak back into the matrix. In addition, an increase in SFAs will decrease polyunsaturation and increase viscosity. n–3 PUFA incorporation into the membrane may also alter protein clustering and enzyme activity, which may alter the amount of ATP produced. Respiratory enzymes are influenced by the increase in n–3 PUFAs and may allow more electrons to escape during oxidative phosphorylation, which will lead to an increase in ROS production and peroxidation. However, n–3 PUFAs can also be cleaved from the membrane via PLA₂ and increase the antioxidant capacity of the mitochondria. In addition, an increase in n–3 PUFAs may release cytochrome c, starting the apoptotic cascade as seen in some cancer models. Overall, FAs through the diet likely have a wide range of different roles within the IMM that require further investigation in both healthy and diseased states. CAT, catalase; CoQ, coenzyme Q; Cyto C, cytochrome c; FUM, fumarate; GPX, glutathione peroxidase; IMM, inner mitochondrial membrane; Pi, inorganic phosphate; PLA₂, phospholipase A₂; SOD, superoxide dismutase; SUCC, succinate.