This review explores the relationship between mitochondrial structure and function in the regulation of macrophage
cholesterol metabolism and proposes that
mitochondrial dysfunction contributes to loss of the elegant homeostatic mechanisms which normally maintain cellular
sterol levels within defined limits. Mitochondrial
sterol 27-hydroxylase (CYP27A1) can generate
oxysterol activators of
liver X receptors which heterodimerise with
retinoid X receptors, enhancing the transcription of
ATP binding cassette transporters (ABCA1, ABCG1, and ABCG4), that can remove excess
cholesterol via efflux to
apolipoproteins A-1, E, and
high density lipoprotein, and inhibit
inflammation. The activity of CYP27A1 is regulated by the rate of supply of
cholesterol substrate to the inner mitochondrial membrane, mediated by a complex of
proteins. The precise identity of this dynamic complex remains controversial, even in steroidogenic tissues, but may include
steroidogenic acute regulatory protein and the 18 kDa translocator
protein, together with
voltage-dependent anion channels,
ATPase AAA domain containing
protein 3A, and
optic atrophy type 1 proteins. Certainly, overexpression of StAR and TSPO
proteins can enhance macrophage
cholesterol efflux to
apoA-I and/or HDL, while perturbations in mitochondrial function, or changes in the expression of mitochondrial fusion
proteins, alter the efficiency of
cholesterol efflux. Molecules which can sustain or improve mitochondrial function or increase the activity of the
protein complex involved in
cholesterol transfer may have utility in resolving the problem of dysregulated macrophage
cholesterol homeostasis, a condition which may contribute to
inflammation,
atherosclerosis,
nonalcoholic steatohepatitis, osteoblastic
bone resorption, and some disorders of the central nervous system.