Abstract
Cardiolipin (CL) is a multifunctional dimeric phospholipid that physically interacts with electron transport chain complexes I, III, and IV, and ATP synthase (complex V). The enzyme ALCAT1 catalyzes the conversion of cardiolipin by incorporating polyunsaturated fatty acids into cardiolipin. The resulting CL species are said to be more susceptible to oxidative damage. This is thought to negatively affect the interaction of cardiolipin and electron transport chain complexes, leading to increased ROS production and mitochondrial dysfunction. Furthermore, it is discussed that ALCAT1 itself is upregulated due to oxidative stress. Here, we investigated the effects of overexpression of ALCAT1 under different metabolic conditions. ALCAT1 is located at the ER and mitochondria, probably at contact sites. We found that respiration stimulated by galactose supply promoted supercomplex assembly but also led to increased mitochondrial ROS levels. Endogeneous ALCAT1 protein expression levels showed a fairly high variability. Artificially induced ALCAT1 overexpression reduced supercomplex formation, further promoted ROS production, and prevented upregulation of coupled respiration. Taken together, our data suggest that the amount of the CL conversion enzyme ALCAT1 is critical for coupling mitochondrial respiration and metabolic plasticity.
Highlights
Cardiolipin (CL) is a unique phospholipid that was first identified in 1947 in beef heart [1]
It was reported that FLAG-tagged acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1) is localized at the ER [8], while another study reported that ALCAT1 is predominantly localized in the mitochondrial-associated membrane [27]
To visualize the ER, we performed immune-staining against KDEL, an ER-localized protein, in addition
Summary
Cardiolipin (CL) is a unique phospholipid that was first identified in 1947 in beef heart [1]. It is known as the mitochondrial signature lipid [2,3,4]. CL is important for mitochondrial function and activity and influences amongst others the electron transport chain (ETC). Mutations in the TAZ1 gene, a protein that is important for the final acyl chain composition of CL, lead to an X-linked disease, called Barth syndrome. The disease is characterized by skeletal and cardiac myopathies and cyclic neutropenia, whereas heart deficiency and opportunistic infections are the main reasons of mortality [2, 7]. CL is a negatively charged phospholipid dimer that consists of two phosphatidic acid molecules connected through glycerol
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