Dr Prajakta Kulkarni's research hopes to unlock potential treatments for Mitochondrial DNA depletion syndrome-13 (MTDPS13). We are supporting her work through a Mito Foundation Research Fellowship. These fellowships support early-career researchers to develop a track record in mito research. Her fellowship is being supervised by Dr Julia Pagan.

What is MTDPS13?

MTDPS13 can be caused by defects in the FBXLA gene, which plays an important role in the maintenance of mitochondrial DNA. Damaged mitochondria need to be removed from cells to function properly. However, a deficiency in FBXLA leads to too many mitochondria being removed. This causes an energy crisis and cell death, resulting in MTDPS13.

Dr Kulkarni is testing whether medicine that blocks mitochondrial removal can treat MTDPS13 disease models. She is using clinically-approved medicines. This means that if her research is successful, it could lead to faster treatment development.

Read our interview with Dr Kulkarni to find out more about her work and this project.

Headshot of Prajakta Kulkarni smiling.

When did you first begin your work in Mito research, and what attracted you to this field?

I have always been interested in translating basic scientific discoveries into clinical applications for the diagnosis, treatment, and prevention of diseases. Mitochondrial dysfunction is linked to a wide range of human diseases, including neurodegenerative disorders (e.g., Parkinson’s and Alzheimer’s disease) and metabolic diseases (e.g., diabetes). Understanding mitochondria is crucial for developing treatments for these conditions. Therefore, I was thrilled to join Dr Julia Pagan’s lab at the University of Queensland, where we study the pathogenesis of mitochondrial diseases. It has been two years since I embarked on this journey to understand mito. Before that, my research was focused on a process called autophagy, which is often impacted in mitochondrial disease, leading to excess or deficient removal of mitochondria. Exploring the intersection between two areas of research has been a stimulating experience.

 

In the time that you’ve researched mito, what are some of your findings that will help the mito community?

Mitochondria are the central producers of cellular energy and, therefore, are fundamental to life and health. Changes in the balance between health and faulty mitochondria can often lead to diseases. One such disorder is Mitochondrial DNA depletion syndrome-13 (MTDPS13) which is caused by changes in the FBXL4 gene. We discovered that FBXL4 prevents MTDPS13 through blocking mitochondrial removal by degrading two important mitophagy substrates, BNIP3 and NIX. Understanding how FBXL4 influences this process could be critical in developing targeted treatments for mitochondrial diseases like MTDPS13.

 

Are there studies or projects that relate to your work or have inspired you?

Identification of ubiquitin ligases, enzymes that help in targeted protein degradation in mitochondrial DNA depletion syndrome, has opened a new avenue for research.

 

How has Mito Foundation helped in your research journey?

Our lab at the School of Biomedical Sciences, University of Queensland, received the 2022 Mito Foundation Incubator Grant. The grant enabled us to organize a cohort of patient cells and purchase putative mitophagy modulatory medications. We established a link between FBXL4, its two mitophagy receptors and mitophagy in a mitochondria DNA depletion syndrome. With the support from the Mito Foundation Research Fellowship, I will have the opportunity to advance my research on how the administration of mitophagy drugs impacts the pathology of MTDPS13 in patient cells.

 

What is your current research focus? 

I am investigating whether restricting mitophagy in MTDPS13 will improve mitochondrial health and functions. We aim to examine whether treating MTDPS13 patient-derived cells with clinically-established inhibitors of autophagy/mitophagy or mitochondrial fission-fusion can lead to the restoration of mitochondrial morphology and functions. The selected drugs will then be tried on a whole animal model. Correlation of genotype and phenotype after specific drug treatments will help towards the development of targeted therapies for specific patients.

 

How have/will you engage with the mito community for this research?

I participated in The Bloody Long Walk in 2023, raising funds for people affected by mito. The long and strenuous walk provided me with a faint glimpse of the challenge people affected by mito endure, leaving me motivated to work towards researching the disease and treatment options.

I look forward to participating in the AussieMit 2024 conference, providing an opportunity to engage with fellow researchers and members of the mito community.

 

If you are able to improve mitochondrial function in your study what will be the next steps for this research?

Our work will involve the use of patient fibroblasts as a model for mitochondrial DNA depletion disease. We intend to use clinically-approved mitophagy modulatory drugs, which aim to inhibit mitophagy and enhance mitochondrial morphology and functions. If so, this is a promising avenue in mitochondrial research as these inhibitors represent possible therapeutic options to restrict mitochondrial removal in the clinical setting of MTDPS13. The use of repurposed FDA-approved drugs will significantly hasten the clinical evaluation of this approach. Identification of novel regulators of FBXL4 mediated mitophagy could increase the repertoire of potential disease targets and aid in designing diagnostic tests. Characterisation of FBXL4 pathogenic variants will help define disease phenotypes better and potentially advance the accuracy as well as patient specificity of the therapy, which might result in an improved quality of life.

 

What else have you seen in the field of mito research that may excite the community?

Drug therapy research and a growing framework of clinical research treatment trials have led researchers to identify better ways to diagnose and treat mito.

A group at Massachusetts General Hospital and Children's Hospital Philadelphia has identified a novel mitochondrial disease with a rare hyperactive mitochondrial phenotype. They have found a gene defective in ATP synthesis. Such cases are important for creating awareness of rare mitochondrial diseases. Researchers are also developing efficient validation assays to support the rapid genetic diagnosis of early and late-onset mito.

It is heartwarming to see and contribute to the efforts of the researchers in the field of mitochondrial research, who continuously unravel the complexities of these organelles and their involvement in human health and disease.