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Mitochondrial citrate carrier SLC25A1 is a dosage-dependent regulator of metabolic reprogramming and morphogenesis in the developing heart

Chiemela Ohanele, Jessica N. Peoples, Anja Karlstaedt, Joshua T. Geiger, Ashley D. Gayle, Nasab Ghazal, Fateemaa Sohani, Milton E. Brown, Michael E. Davis, George A. Porter Jr., Victor Faundez, Jennifer Q. Kwong

Posted on: 12 July 2023 , updated on: 13 July 2023

Preprint posted on 22 May 2023

Powerhouse failure…heartbreaking. Mitochondrial citrate carrier is required for mitochondrial maturation and cardiac development.

Selected by Chee Kiang Ewe, Preethi Krishnaraj

Background:

Mitochondria, the powerhouse of the cell, and its impact on the structural architecture of the heart

In the realm of cardiac development, mitochondria serve as the driving force behind postnatal cardiac metabolism, supplying the energy needed for its contractions. However, the prenatal heart is in a unique and low-oxygen environment where the precise roles of mitochondrial oxidative energy systems remain unclear. What is clear is that mitochondrial metabolism is crucial in embryogenesis, as any dysregulation in this process leads to embryonic death. During the early phases of cardiac development, the mitochondria within the embryonic heart are structurally and functionally immature, relying predominantly on glycolysis to generate ATP. As the heart progresses in its development, studies in mice have observed that around E14.5 the cardiac mitochondria undergo maturation, and embryonic cardiac metabolism transitions towards mitochondrial oxidation (1). This metabolic shift likely facilitates the increasing energy demands of the developing heart, as enhanced oxidative metabolism is a characteristic feature of cardiomyocyte maturation.

In parallel with this metabolic transition, the developing heart undergoes ventricular wall maturation, trabeculation, septation, and compaction. Interestingly, mitochondrial disorders, such as Barth syndrome, MELAS, and MERRF, provide insights into the association between mitochondrial energetics and ventricular morphogenesis. Patients with these disorders often exhibit a congenital heart defect known as left ventricular non-compaction, where the compaction of the ventricular wall is impaired. This suggests a potential link between defects in oxidative phosphorylation and structural malformations of the heart. Although the intricate molecular mechanisms that connect mitochondrial energetics to the precisely regulated process of ventricular wall morphogenesis are yet to be fully understood, exploring these connections could enrich our understanding of cardiac development and offer new genetic targets for enhanced screening and interventions in congenital heart disease.

SLC25A1 – The mitochondrial citrate carrier  

SLC25A1 emerges as a potential link between mitochondrial energetics and other cellular processes. SLC25A1, located in the mitochondrial inner membrane, transports citrate out of the mitochondrial matrix. Its key role consists of supporting mitochondrial oxidative metabolism and the TCA cycle.

In-vitro studies indicate that loss of SLC25A1 affects respiratory functions, suggesting its direct role in regulating mitochondrial functions (2, 3, 4). Moreover, research on 22q11.2 deletion syndrome highlights SLC25A1’s influence on mitochondrial proteins and its contribution to neuropathology (5).

In this study, by employing a systemic Slc25a1 knock-out mouse model, the authors explored SLC25A1’s involvement in the epigenetic regulation of metabolic reprogramming during heart development. Taken together, their findings position SLC25A1 as a novel mitochondrial regulator of cardiac morphogenesis.

Major findings:

  1. Mice lacking Slc25a1 exhibit cardiac structural defects and lethality.

Consistent with previous studies, the authors found that mice lacking Slc25a1 exhibit perinatal lethality. While early Slc25a1-/- embryos are viable, they exhibit impaired growth compared to their Slc25a1+/- and wildtype littermates. All neonatal Slc25a1-/- mice are small and cyanotic as a result of cardiac malformations (as discussed below) and die within 6 hours of birth. The authors found that Slc25a1 is highly expressed in cardiac tissues in embryos. While the morphology of the hearts in Slc25a1-/- mice are largely normal in early embryos (E10.5), severe cardiac abnormalities become evident as cardiac morphogenesis progresses. Importantly, the authors found that Slc25a1+/- embryos also display a higher frequency of cardiac malformation and die shortly after birth. Indeed, Slc25a1 expression is significantly reduced in Slc25a1+/- embryos. However, a fraction of the heterozygous mice survives to adulthood.

  1. Loss of Slc25a1 causes mitochondrial dysfunction and metabolic defects.

Given the role of SLC25a1 in mitochondrial oxidative metabolism, the authors examined changes in metabolic gene expression in embryos lacking one or both copies of Slc25a1 using a NanoString mRNA quantification panel. This analysis showed that many genes involved in mitochondrial functions, such as oxidative phosphorylation, glycolysis, hypoxia, and fatty acid metabolism, were differentially expressed in Slc25a1+/- and Slc25a1-/-. Both Slc25a1+/- and Slc25a1-/- mutants exhibited mitochondrial dysfunction, though Slc25a1-/- embryos showed a more severe phenotype.

Next, the authors examined the ultrastructure of mitochondria in the mutant embryonic hearts using transmission electron microscopy. They found that the mitochondria in Slc25a1+/- and Slc25a1-/- are swollen and larger compared to wildtype hearts. They also contain highly immature and disordered cristae as well as open matrix voids. Again, Slc25a1-/- showed a more severe phenotype compared to Slc25a1+/-, indicating Slc25a1’s dose-dependent effects.

Consistent with earlier observations, the authors found that coupled mitochondrial oxygen consumption in Slc25a1+/- and Slc25a1-/- hearts is substantially decreased compared to Slc25a1+/+. While the copy number of mitochondria was not reduced in the mutants, respiratory chain complex subunits were significantly downregulated in Slc25a1+/- embryonic hearts. Together, these results indicate that loss of Slc25a1 impairs oxidative phosphorylation in a dose-dependent manner. Indeed, by performing targeted gas chromatography–mass spectrometry (GC-MS) metabolomic profiling, the authors showed that citrate fails to be incorporated into the TCA cycle in the mutants, thereby limiting oxidative metabolism. Furthermore, through computational modelling, the authors showed that the loss of Slc25a1 blocks the progression of mitochondrial maturation and metabolic reprogramming during cardiac development. This occurs as the heart transitions from dependence on glycolysis to oxidative phosphorylation.

  1. Loss of Slc25a1 reduces H3K9ac at the Pparg

To further investigate the regulatory mechanism by which Slc25a1 affects metabolism in the developing heart, the authors performed transcription factor analysis and found peroxisome proliferator activated receptor gamma (PPARγ) as the top candidate that regulates Slc25a1-dependent metabolic genes. PPARγ is known to be a key player in glucose metabolism. The authors found that Pparg is downregulated in Slc25a1-/+ and Slc25a1-/-, compared to wildtype. Supporting the role of mitochondrial metabolism in epigenetic regulation, H3K9ac levels (a hallmark of gene activation) were markedly reduced in the Slc25a1 mutants. Importantly, the authors showed that H3K9ac levels are reduced at the Pparg promoter in Slc25a1+/- and Slc25a1-/- hearts compared to Slc25a1+/+ embryonic hearts. Hence, the authors proposed a model in which SLC25A1-mediated citrate export is crucial for the production of acetyl-CoA in the cytosol, which is subsequently used for the deposition of H3K9ac on Pparg and impacts metabolic gene expression important for proper heart development (Figure 1).

Figure 1: A model illustrating the involvement of SLC25A1 in the regulation of metabolic gene expression in the developing heart (see text). Modified from Figure 7, Ohanele, et al. (2023)

What we liked about this preprint:

The authors combined transcriptomics, biochemistry, metabolomics, and mathematical modelling to study the roles of Slc25a1 in mitochondrial maturation and embryonic heart development. This study is very thorough and comprehensive. Understanding the mechanism by which mitochondrial signalling influences the epigenetic landscape and metabolic gene expression during heart development offers important implications for cardiac embryology and pathology.

Questions for the authors:

  1. What is the phenotype of mice lacking Pparg? Do they also show cardiac structural defects?
  2. Do you know if the cardiac progenitors are correctly differentiated in Slc25a1-/-? We wonder whether citrate export also affects cell fate.
  3. Have you looked into other paralogs of Slc25a1 in the mutants?

References:

  1. Zhao, Q., Sun, Q., Zhou, L., Liu, K., and Jiao, K. (2019). Complex Regulation of Mitochondrial Function During Cardiac Development. J Am Heart Assoc.
  2. Fernandez, H.R., Gadre, S.M., Tan, M., Graham, G.T., Mosaoa, R., Ongkeko, M.S., Kim, K.A., Riggins, R.B., Parasido, E., Petrini, I., et al. (2018). The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer. Cell Death Differ
  3. Fernandez, H.R., Gadre, S.M., Tan, M., Graham, G.T., Mosaoa, R., Ongkeko, M.S., Kim, K.A., Riggins, R.B., Parasido, E., Petrini, I., et al. (2018). The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer. Cell Death Differ
  4. Wynne, M.E., Ogunbona, O., Lane, A.R., Gokhale, A., Zlatic, S.A., Xu, C., Wen, Z., Duong, D.M., Rayaprolu, S., Ivanova, A., et al. (2023). APOE expression and secretion are modulated by mitochondrial dysfunction. Elife.
  5. Unolt, M., Versacci, P., Anaclerio, S., Lambiase, C., Calcagni, G., Trezzi, M., Carotti, A., Crowley, T.B., Zackai, E.H., Goldmuntz, E., et al. (2018). Congenital heart diseases and cardiovascular abnormalities in 22q11.2 deletion syndrome: From well-established knowledge to new frontiers. Am J Med Genet A.

Tags: embryonic heart, metabolism, slc25a1

doi: https://doi.org/10.1242/prelights.35055

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