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Chicco 2023 MiP2023

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MiPschool 2023

Chicco 2023 MiP2023

Chicco Adam J
Delta-6 desaturase inhibition reverses aberrant cardiolipin remodeling and mitochondrial dysfunction in the obese mouse heart.

Link: MiP2023 Obergurgl AT

Chicco Adam J (2023)

Event: MiP2023 Obergurgl AT

Authors: Chicco Adam J, Le Catherine H, Mulligan Christopher M, Whitcomb Luke A, Evans Amanda E, Routh Melissa A, Sparanga Genevieve C

Cardiolipin (CL) is a tetra-acyl mitochondrial phospholipid that supports the optimal function of several mitochondrial membrane proteins and processes. In the healthy mammalian heart, the majority of CL species contain four linoleate acyl chains (L4CL). A marked depletion of cardiac L4CL is paralleled by an increase in CL species containing docosahexaenoic acid (DHA) in hyperphagic obese (Lepob; OB) mice despite no change in dietary fat composition [1], but the mechanisms and functional relevance of these changes are unclear. We hypothesized that this shift in CL composition results from increased activity of delta-6 desaturase (D6D), the rate limiting enzyme in the biosynthesis of DHA and conversion of linoleate into highly unsaturated Ο‰-6 fatty acids, by altering the distribution of fatty acids available for CL remodeling. To test this, we administered the selective D6D inhibitor SC-26196 (100 mg/kg/d in chow) to 4-5 month-old OB or lean (C57Bl/6) mice for 4 weeks. As hypothesized, D6D inhibition reversed obesity-related changes in cardiac CL composition, restoring L4CL and DHA-enriched CL species to within 5 % of levels in lean mice, which paralleled reciprocal shifts in the linoleate and DHA levels of total myocardial phospholipids. Obesity-related decreases in cardiac mitochondrial respiratory control by ADP (with NS pathway substrates) and greater mitochondrial H2O2 release during both LEAK and OXPHOS states were also abolished by D6D inhibition. These results corroborate accumulating evidence that cardiac CL composition is strongly influenced by the membrane fatty acids available for CL remodeling [2-3], and may impact the bioenergetic efficiency of mitochondrial respiration.

  1. Han X, Yang J, Yang K, ZhongdancZ, Abendschein DR, Gross RW (2007) Alterations in Myocardial Cardiolipin Content and Composition Occur at the Very Earliest Stages of Diabetes:  A Shotgun Lipidomics Study Biochemistry
  2. Le CH et al. (2014) Delta-6-desaturase links PUFA metabolism with phospholipid remodeling and disease progression in heart failure.
  3. Oemer G, Edenhofer ML, Wohlfarter Y, Lackner K, Leman G, Koch J, Cardoso LHD, Lindner HH, Gnaiger E, Dubrac S, Zschocke J, Keller MA (2021) Fatty acyl availability modulates cardiolipin composition and alters mitochondrial function in HeLa cells.

β€’ Keywords: cardiolipin; polyunsatruated fatty acids; membrane composition; obesity; uncoupling

β€’ O2k-Network Lab: US CO Fort Collins Chicco AJ


Chicco Adam J1-4, Le Catherine H2, Mulligan Christopher M3, Whitcomb Luke A1, Evans Amanda E1, Routh Melissa A2, Sparanga Genevieve C4
  1. Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
  2. Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA
  3. Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA
  4. Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA
Corresponding author: [email protected]

Labels: Pathology: Obesity 

Organism: Mouse 

Regulation: Fatty acid 

Event: Oral