Treatment Strategies for Mitochondrial Disease

This Focused Program Award (FPA) application is being submitted in response to the Fiscal Year 2019 Peer Review Peer Reviewed Medical Research Program Topic Area of Mitochondrial Disease. Mitochondria are tiny bacterium-sized organelles located in essentially every cell of the body. While they have many functions, mitochondria have often been called the 'powerhouse of the cell' because of their critical and central role in producing approximately 90% of the energy required for cells to be viable and to perform their functions properly. As one can well imagine, if something goes wrong with the machinery running this 'bioenergetic' factory, cells, and especially those with high energy demands, such as brain, heart, and muscle, begin to 'run out of gas' and will eventually die. In the last 30 years, a revolution has taken place in our understanding of the cause of disease due to defective energy production, now called 'mitochondrial disease.' Specifically, we now understand that there are inherited mutations, both in nuclear genes and in mitochondrial genes (besides the nucleus, mitochondria have their own private DNA, called mtDNA) that are required to build the energy generating (oxidative phosphorylation [OxPhos]) machines. These mutations can cause the machines to misfire, resulting in the energy starvation that is a hallmark of mitochondrial diseases. As of today, about 200 mutations in mtDNA, and an equal but growing number in nuclear DNA, have been found to be responsible for these diseases. While we have made great strides in understanding etiology (i.e., what causes a disease – in this case the specific genes that are mutated), our understanding of pathogenesis (i.e., how the mutation results in the symptoms and progression of the disease) has lagged behind, and because we have difficulty in understanding pathogenesis, our insight into how to treat, and ultimately cure, mitochondrial disease is correspondingly inadequate. Put another way, to know how to treat, we have to know what to treat. That is the overarching challenge that we propose to address in this FPA application. For over 30 years, the Columbia mitochondrial group has been a leader in the study of mitochondrial disease, in all of its aspects: clinical science, basic science, and genetics. We have assembled a set of skilled investigators whose goal is to advance our understanding of mitochondrial disease, from both a basic biology and clinical point of view, with the ultimate goal of treating these disorders. Specifically, we propose five distinct, but interconnected projects. Project 1 will build upon a 20-year effort to document the 'natural history' (how patients fare, from the earliest onset of the disease to the end of life) of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). This long-term project has now reached the point where we will initiate a clinical trial to assess the role of a compound called N-acetyl cysteine (NAC) in mitigating the severity of the disease, especially in the brain and assess biomarkers. Project 2 will build on new findings regarding the way mitochondria communicate with the rest of the cell – specifically with the endoplasmic reticulum (ER) (the cell's 'post office'). In mitochondrial disease, ER-mitochondrial communication is disrupted, resulting in alterations in key metabolic pathways that we know are perturbed in mitochondrial disease. We will try to understand how this 'decoupling' occurs, and then use genetic and pharmacological methods to bring ER and mitochondria 'back together,' in a completely new approach to treating mitochondrial diseases. Project 3 will assess the role of coenzyme Q, a key component of the OxPhos machinery, in affecting the formation of 'free radicals' that, in excess, can damage cellular components, including molecules that are the targets of NAC in Project 1. Project 4 will focus on treating mouse models that recapitulate the features