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Mejia et al. J Transl Genet Genom 2024;8:216-24 https://dx.doi.org/10.20517/jtgg.2024.11 Page 222

It would be intriguing to examine creatine uptake and whether localization of PKCδ within a higher
molecular weight complex in mitochondria is impaired in cells of multi-system mitochondrial disease
patients with CL synthase (CRLS1) dysfunction in which loss of CL and phosphatidylglycerol accumulation
[30]
results in fragmented mitochondrial morphology and bioenergetic dysfunction . This might address
whether the accumulation of MLCL is responsible for our observations.

Although much has been learned on regulation of cellular metabolism and the immune response from
Epstein-Barr virus transformed B lymphoblasts since the discovery of the first human tumor virus by
[31]
Epstein, Achong and Barr 60 years ago , caution should be exercised in interpretation of our results as the
transformed nature of these cells has been shown to modify both expression and alternative splicing of host
cell genes [32,33] .

CONCLUSION
We conclude that impaired localization of PKCδ within a higher molecular weight complex in mitochondria
may contribute to the bioenergetic defects observed in BTHS B lymphoblasts and enhanced creatine uptake
may serve as a compensatory mechanism for the defective mitochondrial oxidative phosphorylation
observed in these cells.

DECLARATIONS
Acknowledgments
We thank Dr. Fred Y. Xu for technical assistance.

Authors’ contributions
Performed experiments: Mejia EM, Sparagna GC
Conceptual design: Miller DW, Hatch GM
Wrote the manuscript: Hatch GM
All authors read and edited the manuscript.

Availability of data and materials
All data supporting the findings can be found within the manuscript.

Financial support and sponsorship
This work was supported by grants from the Natural Sciences and Engineering Research Council (NSERC)
(RGPIN-05368-2019 to Hatch GM) and the National Institutes of Health (NIH) USA (P30DK048520 to
Sparagna GC). Mejia EM was supported by a Manitoba Health Research Council studentship. Hatch GM
was the Canada Research Chair in Molecular Cardiolipin Metabolism.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Research involving human control and BTHS B lymphoblasts was performed in accordance with the
Declaration of Helsinki with approval from the University of Manitoba Environmental Health and Safety
Office (Biological Safety Project Approval Certificate #BB0044-2). Epstein-Barr virus transformed BTHS B
lymphoblasts from 4- to 9-year-old males and male age-matched control lymphoblasts were a generous gift
from Dr. Richard Kelley, Kennedy Kreiger Institute, Baltimore, MD., and obtained from Coreill Institute
(Camden, NJ).