Our lab studies the cellular mechanisms involved in mitochondrial repair. One approach to mend distressed mitochondria is through the activation of the protective pathway known as the mitochondrial unfolded protein response (UPRmt). A central regulator of the UPRmt is ATFS-1, a transcription factor whose activation largely depends on the import efficiency of mitochondria (Figure 1). ATFS-1 contains targeting sequences that can direct it to both mitochondria and nuclei. ATFS-1 is imported into mitochondria when the organelle is healthy where it is inactivated via proteolytic degradation. However, import efficiency into the mitochondria is reduced when the organelle is dysfunctional thus allowing ATFS-1 to traffic to the nucleus where it regulates a broad mitochondrial protective transcriptional response (see Nargund*, Pellegrino* et al. Science 2012).

Figure 1. The UPRmt is regulated by the transcription factor ATFS-1

Research Aims

The following are some of the research areas that we are actively pursuing.

1. Identify the molecular mechanisms used to regulate the UPRmt

We primarily use the model organism Caenorhabditis elegans to study the UPRmt because it is easy to manipulate and possesses molecular pathways that are conserved with humans. Specifically, we use a transgenic strain of C. elegans that contains a fluorescent reporter expressing green fluorescent protein (GFP) that allows us to very easily score UPRmt activation (Figure 2). When mitochondria are healthy and the UPRmt is in the OFF state the worm barely displays fluorescence. In contrast, conditions that perturb mitochondrial function and activate the UPRmt causes a dramatic increase in the fluorescence of the UPRmt GFP reporter that is ATFS-1-dependent. We will use the power of C. elegans genetics to identify novel regulators of the UPRmt using this robust in vivo reporter system. Once identified, we will then test the function of their mammalian homologs using cell culture and mammalian model systems.

2. Examine the role of the UPRmt in host-pathogen interactions

We also made the remarkable discovery that certain disease-causing bacteria that produce toxins and virulence factors that impair mitochondrial function, such as the opportunistic pathogen Pseudomonas aeruginosa, can activate the UPRmt (Figure 3). Amazingly, in addition to regulating genes that repair the function of mitochondria, we unexpectedly discovered that ATFS-1 controls the expression of immunity genes that protect the host from those harmful pathogens (see Pellegrino et al. Nature 2014). We now wish to identify the factors produced by these pathogens that target mitochondrial function and modulate the activity of the UPRmt during infection.

3. Investigate the function and therapeutic potential of the UPRmt in human disease

The essential nature of mitochondria is often reflected in the vast number of diseases that manifest when the function of the organelle is impaired. Neurological diseases, cancer, and diabetes are just a few of the many pathologies associated with mitochondrial dysfunction. The main purpose of the UPRmt is to repair damaged mitochondria making this an ideal pathway to target for potential therapeutic strategies (Figure 4).

 Figure 2. The hsp-6pr::GFP transgene acts as a reporter for UPRmt activity in C. elegans.

Figure 3. The UPRmt is activated during infection with pathogens such as Pseudomonas aeruginosa.

Figure 4. The UPRmt is required for viability of cancer cells such as the thyroid oncocytic cell line XTC.UC1. 

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