Pilot-Storck 2022 Abstract Bioblast

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Prola A, Khadhraoui N, Vandestienne A, Blondelle J, Wintrebert M, Tiret L, Pilot-Storck Fanny (2022) Hacd1 and Hacd2 genes control mitochondrial energetic efficiency through the modulation of mitochondrial membranes phospholipid composition. Bioblast 2022: BEC Inaugural Conference.

Link: Bioblast 2022: BEC Inaugural Conference

Prola Alexandre, Khadhraoui N, Vandestienne A, Blondelle J, Wintrebert M, Tiret L, Pilot-Storck Fanny (2022)

Event: Bioblast 2022

Mitochondrial energy efficiency involves optimal coupling between oxidative processes and ADP phosphorylation, which implies an advanced structure-function relationship of the inner mitochondrial membrane (IMM). Alteration of this oxidative phosphorylation process can lead to mitochondrial disease, as in the case of mutations of the HACD1 gene which cause a congenital myopathy characterized by muscle weakness and exercise intolerance [1].

We generated mutant mice for Hacd1 gene as well as its close paralog, Hacd2 gene that shares high structural and functional similarity with Hacd1.

We identified that Hacd1-deficient mice present a muscle-specific twofold reduction in OXPHOS coupling. This alteration of mitochondrial efficiency blunts ATP production during exercise and leads to increased lactate accumulation. However, it also increases energy expenditure at rest and as such, confers a protection to Hacd1-deficient mice from diet-induced obesity [2]. HACD1 (3-hydroxyacyl-coenzyme A dehydratase, member 1) is part of the synthetic pathway of very long chain fatty acids, i.e., fatty acids comprising 18 carbons or more [3]. In Hacd1-deficient mice, mitochondrial phospholipid content is halved, with the IMM-specific cardiolipin being the most affected. This defect is associated with cristae dilation, and we demonstrated that cardiolipin enrichment of isolated mitochondria from Hacd1-deficient mice was sufficient to restore OXPHOS coupling. Hacd1 deficiency thus reveals that cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle [2].

In parallel, the Hacd2 gene exhibits an early and broad expression and we identified that a reduction of its expression leads to cachexia and ultimately death of mice during their first month of life. This devastating condition is associated with elevated lactate levels and impaired mitochondrial coupling in the kidney and liver [4]. We further show that complete loss of Hacd2 expression is associated with major cardiovascular malformations and lethality at mid-embryonic development. In mutant embryos, mitochondria show compartmentalization and high amounts of oxidized cardiolipin, as well as a strong reduction in OXPHOS coupling efficiency [4].

In conclusion, our studies reveal that mutations in Hacd1 and Hacd2 genes lead to muscle-specific or systemic mitochondrial diseases, respectively, prompting the screening of their mutation for patients suffering from orphan mitochondrial diseases. Our work further reveals that Hacd1 and Hacd2 genes are new actors in the genetic control of mitochondrial membrane phospholipid composition and hence, mitochondrial energetic efficiency.

Keywords: OXPHOS, Cardiolipin, Myopathy, Mitochondrial disease, Very long chain fatty acids Bioblast editor: Plangger M


Affiliations

Univ Paris Est Creteil, EnvA, IMRB, Team Relaix, F-94700 Maisons-Alfort, France. - fanny.storck@vet-alfort.fr

References

  1. Abbasi-Moheb L, Westenberger A, Alotaibi M, Alghamdi MA, Hertecant JL, Ariamand A, Beetz C, Rolfs A, Bertoli-Avella AM, Bauer P (2021) Biallelic loss-of-function HACD1 variants are a bona fide cause of congenital myopathy. Clinical Genetics 99:513-8. doi:10.1111/cge.13905
  2. Prola A, Blondelle J, Vandestienne A, Piquereau J, Denis RGP, Guyot S, Chauvin H, Mourier A, Maurer M, Henry C, Khadhraoui N, Gallerne C, Molinié T, Courtin G, Guillaud L, Gressette M, Solgadi A, Dumont F, Castel J, Ternacle J, Demarquoy J, Malgoyre A, Koulmann N, Derumeaux G, Giraud MF, Joubert F, Veksler V, Luquet S, Relaix F, Tiret L, Pilot-Storck F (2021) Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle. Science Advances 7:eabd6322. doi:10.1126/sciadv.abd6322
  3. Ikeda M, Kanao Y, Yamanaka M, Sakuraba H, Mizutani Y, Igarashi Y, Kihara A (2008) Characterization of four mammalian 3-hydroxyacyl-CoA dehydratases involved in very long-chain fatty acid synthesis. FEBS Letters 582:2435–2440 (2008). doi:10.1016/j.febslet.2008.06.007
  4. Khadhraoui N et al (in preparation) Hacd2 deficiency leads to an early and lethal mitochondrial disease.

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