Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression

Li, Jia; Liu, Xiaolei; Wang, Huayan; Zhang, Weiping; Chan, David C.; Shi, Yuguang

doi:10.1073/pnas.1120043109

Cited by 84 publications

(71 citation statements)

References 35 publications

(54 reference statements)

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“…This observation complements the well-established data linking morbidity and reduced CL by showing that there exists a range of mitochondrial changes in which CL undergoes a potentially compensatory response and a range (e.g., phosphatidylethanolamine and phosphatidylcholine) to MLCL via a phospholipid-lysophospholipid transacylase termed tafazzin (64)(65)(66)(67)(68)(69)(70).…”

Section: More Than a Target-regulated Response To Environmental Infl supporting

confidence: 81%

Dietary macronutrients modulate the fatty acyl composition of rat liver mitochondrial cardiolipins

Stavrovskaya

Bird

Marur

et al. 2013

Journal of Lipid Research

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Supplementary key words mitochondria • ubiquinones • saturated fatty acids • trans fatty acids • monounsaturated fatty acids • polyunsaturated fatty acids • glycemic index • lipidomicsCardiolipins (CLs) are a subclass of phospholipids unique to mitochondria. Each CL is a dimeric phospholipid consisting of two phosphatidyl head groups, connected on a glycerol backbone, and four fatty acyl chains ( 1-3 ). Unlike most membrane phospholipids, CLs are predominantly found in the mitochondrial inner membrane and at contact sites between the inner and outer mitochondrial membrane. CLs comprise ‫ف‬ 25% of total phospholipids in the mitochondrial inner membrane ( 1-3 ). Mammalian CL has been reported to contain primarily ( ‫ف‬ 85%) 18:2 (linoleic) acyl side chains ( 2, 4, 5 ) that mediate the high affi nity of CL to inner mitochondrial membrane proteins ( 3, 6, 7 ).CLs play multiple key roles in the regulation of mitochondrial metabolism ( 2, 3, 8-10 ). These functions include maintenance of proper mitochondrial quaternary structure, regulation of essential enzymatic activities involved in electron transport and oxidative phosphorylation, and assembly of respiratory supercomplexes. In particular, CL is required for the proper functioning of mitochondrial respiratory complexes I, III, IV (cytochrome oxidase), ATP synthase ( 6,(11)(12)(13)(14)(15)(16)(17)(18)(19), cardiolipin synthase ( 20 ), and several transporters in the inner mitochondrial membrane [e.g., the ADP/ATP translocator ( 10, 18, 21 ), phosphate transporter ( 22 ), pyruvate transporter ( 23 ), and carnitine/ acylcarnitine carrier ( 24 )

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Section: More Than a Target-regulated Response To Environmental Infl supporting

confidence: 81%

Dietary macronutrients modulate the fatty acyl composition of rat liver mitochondrial cardiolipins

Stavrovskaya

Bird

Marur

et al. 2013

Journal of Lipid Research

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“…Targeted inactivation of ALCAT1 prevents mitochondrial dysfunction and the onset of obesity, which is a major causative factor for type 2 diabetes and cardiovascular diseases (4). Additionally, we have recently demonstrated a key role of oxidative stress caused by ALCAT1 in mitochondrial fragmentation, a common defect associated with mitochondrial dysfunction in age-related metabolic diseases (23). Together, these findings suggest that development of inhibitors of ALCAT1 may provide novel treatments for cardiac hypertrophy and other heart diseases, which comprise the major cause of fatality in developed countries.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, targeted inactivation of ALCAT1 prevents the onset of diet-induced obesity and its related metabolic complications (24). Additionally, ALCAT1 deficiency also improves mitochondrial quality control and mitochondrial DNA (mtDNA) fidelity by preventing the mitochondrial fusion defect commonly associated with age-related metabolic diseases (23). Furthermore, CL remodeling by ALCAT1 is also implicated in the pathogenesis of mitochondrial dysfunction in cardiomyopathy, since ALCAT1 expression in the heart is significantly upregulated by hyperthyroidism and downregulated by hypothyroidism (6).…”

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confidence: 99%

Ablation of ALCAT1 Mitigates Hypertrophic Cardiomyopathy through Effects on Oxidative Stress and Mitophagy

Liu

Miller

et al. 2012

Molecular and Cellular Biology

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Oxidative stress causes mitochondrial dysfunction and heart failure through unknown mechanisms. Cardiolipin (CL), a mitochondrial membrane phospholipid required for oxidative phosphorylation, plays a pivotal role in cardiac function. The onset of age-related heart diseases is characterized by aberrant CL acyl composition that is highly sensitive to oxidative damage, leading to CL peroxidation and mitochondrial dysfunction. Here we report a key role of ALCAT1, a lysocardiolipin acyltransferase that catalyzes the synthesis of CL with a high peroxidation index, in mitochondrial dysfunction associated with hypertrophic cardiomyopathy. We show that ALCAT1 expression was potently upregulated by the onset of hyperthyroid cardiomyopathy, leading to oxidative stress and mitochondrial dysfunction. Accordingly, overexpression of ALCAT1 in H9c2 cardiac cells caused severe oxidative stress, lipid peroxidation, and mitochondrial DNA (mtDNA) depletion. Conversely, ablation of ALCAT1 prevented the onset of T4-induced cardiomyopathy and cardiac dysfunction. ALCAT1 deficiency also mitigated oxidative stress, insulin resistance, and mitochondrial dysfunction by improving mitochondrial quality control through upregulation of PINK1, a mitochondrial GTPase required for mitochondrial autophagy. Together, these findings implicate a key role of ALCAT1 as the missing link between oxidative stress and mitochondrial dysfunction in the etiology of age-related heart diseases.

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“…Localized in the mitochondrion (mt)-associated membrane, ALCAT1 catalyzes the pathological remodeling of cardiolipins in response to oxidative stress in diabetes, obesity, and cardiomyopathy, leading to reactive oxygen species production, mt dysfunction, and insulin resistance (63,64). Moreover, ALCAT1 overexpression is responsible for mt fusion defects or mt DNA instability (65).…”

Section: Fig 12mentioning

confidence: 99%

Requirement of Phosphoinositides Containing Stearic Acid To Control Cell Polarity

Doignon

Laquel

Testet

et al. 2016

Molecular and Cellular Biology

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c Phosphoinositides (PIPs) are present in very small amounts but are essential for cell signaling, morphogenesis, and polarity. By mass spectrometry, we demonstrated that some PIPs with stearic acyl chains were strongly disturbed in a psi1⌬ Saccharomyces cerevisiae yeast strain deficient in the specific incorporation of a stearoyl chain at the sn-1 position of phosphatidylinositol. The absence of PIPs containing stearic acid induced disturbances in intracellular trafficking, although the total amount of PIPs was not diminished. Changes in PIPs also induced alterations in the budding pattern and defects in actin cytoskeleton organization (cables and patches). Moreover, when the PSI1 gene was impaired, a high proportion of cells with bipolar cortical actin patches that occurred concomitantly with the bipolar localization of Cdc42p was specifically found among diploid cells. This bipolar cortical actin phenotype, never previously described, was also detected in a bud9⌬/bud9⌬ strain. Very interestingly, overexpression of PSI1 reversed this phenotype. Lipids are not limited to the simple role of being components of biological membranes for cell compartmentalization. On the basis of their structural diversity, they are also biologically active molecules regulating several important physiological functions. Lipids can be classified into eight broad categories, on the basis of well-defined chemical and biochemical principles, with distinct functions in cells (1). Among them, phosphatidylinositol-4-phosphate [PI(4)P] and phosphatidylinositol-4,5-diphosphate [PI(4,5)P 2 ], derived from phosphatidylinositol (PI) by a series of kinase reactions, play major roles, even though they are minor constituents of cellular membranes; e.g., in the yeast Saccharomyces cerevisiae, PI represents about 20% of total phospholipids (2) and phosphatidylinositol phosphates (PIPs) represent only 0.1 to 1.1% of PIs (3, 4). It has been established that some mutations in genes encoding PIP-metabolizing enzymes are responsible for human diseases (Lowe syndrome, myopathy, Charcot-Marie-Tooth disease, psychiatric diseases, diabetes, cancer, Alzheimer's disease, etc.) (5). In addition, previous studies have demonstrated the role of PIPs in the control of cell polarity (by acting on actin cytoskeleton dynamics), secretory pathways, and septin recruitment and organization in animals, plants, and yeasts (6-11). Nevertheless, most studies pointing out a specific role for PIPs are related to the polar head groups and not to the fatty acid component, even though PIs from plants, animals, and yeast contain larger amounts of saturated fatty acids than other phospholipids (12). Only a few studies have highlighted the importance of the acyl chain composition of PIPs, for example, the nature of the acyl chains associated with PI(4,5)P 2 for activation of the GIRK1/GIRK4 potassium channel (13,14), and the importance of saturated fatty acids associated with PIPs to address these lipids in plant lipid rafts (15). In S. cerevisiae, stearic acid accounts for a few p...

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Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression

Cited by 84 publications

References 35 publications

Dietary macronutrients modulate the fatty acyl composition of rat liver mitochondrial cardiolipins

Dietary macronutrients modulate the fatty acyl composition of rat liver mitochondrial cardiolipins

Ablation of ALCAT1 Mitigates Hypertrophic Cardiomyopathy through Effects on Oxidative Stress and Mitophagy

Requirement of Phosphoinositides Containing Stearic Acid To Control Cell Polarity

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