Regulation of mitochondrial size, number and function

Fission and fusion of mitochondria regulate their size, biogenesis and clearance, thus maintaining an organism’s healthy pool of mitochondria. With the help of an unbiased genetic screen using Drosophila, we identified several genes that regulate mitochondrial dynamics and biogenesis. This screen allowed us to address some fundamental questions, such as – how mitochondrial size is regulated under various physiological conditions and developmental stages and how mitochondrial abundance is regulated during development and metabolic stress.
In recent work, we identified that under mitochondrial stress, K63-linked ubiquitin ligase Bendless, a homolog of human Ube2N, is required to stabilise PINK1. The protein PINK1 has been known to regulate mitochondrial quality control and has been associated with Parkinson’s disease.

Mito-Nuclear communication

Through an unbiased genetic screen in flies, we have identified mutations that induce metabolic stress and mitochondrial biogenesis through a mitochondrial retrograde signaling pathway. Though stress-induced mitochondrial biogenesis has been observed in patients with mitochondrial diseases, it is unclear how this is triggered and consequently may be contributing to the pathogenesis. Using our collection of mutants, we are investigating the mechanism of mito-nuclear communication that changes the transcription of genes to promote stress-induced mitochondrial biogenesis. We use comparative genomics, genetics and bioinformatics to identify transcription factors and other players involved in this process. The genetic screen has fed several attractive candidates to our pipeline to keep us busy.

Biology of Polyphosphates

Polymers of inorganic phosphates, polyP, exist in all life forms. Their function in metazoans is unclear, but circumstantial evidence suggests its involvement in many biological processes. To systematically investigate the biological function of polyP, we began with developing tools to quantify and manipulate polyP in flies. We will keep exploring phenotypes linked to polyP manipulation to know its biological functions. Due to the interdisciplinary nature of this work, we collaborate with biochemists, chemical biologists and biophysicists. Our collaborators are Kalyaneswar Mandal (TIFR Hyderabad), Kaustubh Mote (TIFR Hyderabad), Anand T Vaidya (TIFR Hyderabad), Rashna Bhandari (CDFD Hyderabad) and Henning J Jessen (Albert-Ludwigs-University, Freiburg, Germany).

Metabolic signaling and development – connecting Down syndrome with TOR

The cellular metabolic state can determine cell fate, physiology and survival. TOR pathway is one of the pathways that can integrate cellular metabolic signaling to determine the growth and fate of the cell. TOR is also implicated in several diseases, including cancer and age-related disorders. In a collaborative work, we identified that the Down syndrome linked gene DYRK1A is a positive regulator of the TOR. This interaction is conserved in flies. minibrain, the DYRK1A homolog in flies, positively regulates TOR and, thereby, the development of neuromuscular junctions. This work provided new links to Down Syndrome. We will continue to work on the DYRK1A-TOR axis to know more about the metabolic regulation of DYRK1A/Mnb and Down Syndrome.