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Background Mitochondrial respiration is reduced in atherosclerotic plaques, but the factors that drive this are unclear. Tafazzin, a mitochondrial transacylase, is essential for the maturation of cardiolipin, a key component of the inner mitochondrial membrane. However, the role of tafazzin in regulating macrophage function and its contribution to atherosclerosis is unknown.Objectives To characterise macrophage tafazzin expression and regulation in atherosclerotic plaquesTo examine how tafazzin influences macrophage functionTo investigate the effect of macrophage tafazzin on atherogenesisMethods Tafazzin expression and its regulation were examined in human atherosclerotic plaques and THP-1 macrophages. Tafazzin function was investigated by siRNA silencing in THP-1 macrophages. Apolipoprotein E deficient ( ApoE-/-) mice overexpressing enzymatically inactive tafazzin (TazH69Q) or functional tafazzin (Taz+) under the CD68 macrophage promoter were generated for in vivo and in vitro analysis.Results Tafazzin mRNA expression was decreased in human plaques compared to normal aortic tissue. Immunohistochemistry showed decreased tafazzin expression in CD68 + macrophages in human plaque cores. Both native and oxidised low density lipoprotein induced miR-125a-5p in THP-1 macrophages and decreased tafazzin mRNA and protein levels. Furthermore, in situ hybridisation demonstrated elevated miR-125a-5p expression in CD68+ plaque core macrophages. Silencing tafazzin in THP-1 macrophages reduced mitochondrial respiration and mitochondrial membrane potential while increasing oxidative stress. Macrophages from CD68-TazH69Q/ApoE-/- mice exhibited decreased respiration and efferocytosis yet had increased IL-1β release and mitochondrial oxidative stress. However, IL-1β and oxidative stress were reduced in CD68-Taz+/ApoE-/- macrophages. After 14 weeks of high fat diet, aortic plaque area was increased in ApoE-/- mice transplanted with CD68-TazH69Q/ApoE-/- bone marrow yet decreased in CD68-Taz+/ApoE-/- recipients compared to mice transplanted with ApoE-/- control marrow.Conclusion Our findings demonstrate that tafazzin is critical for macrophage function and is regulated by miR-125a-5p. Loss of macrophage tafazzin function promotes mitochondrial dysfunction, inflammation and atherosclerosis. Tafazzin downregulation in plaque macrophages may be an important factor in disease progression, offering new insights into the mechanisms underlying atherogenesis