Role of MNRR1 as a Therapeutic Target in Mitochondrial Disease Models
Abstract
PRMRP Topic Area: Mitochondrial Disease Energy is the currency of the cell and regulating its supply and its use has come to be seen as perhaps the most crucial activity the cell can engage in. The objectives of this proposal, broadly speaking, are to be able to help individuals with mitochondrial disease – both overt, primary mitochondrial diseases, as well as diseases such as Parkinson’s in which mitochondrial dysfunction plays a role, and in which improving mitochondrial function would improve health. Specifically, we uncovered a gene, MNRR1, that has turned out to be a major regulator of mitochondrial function and stress response. We demonstrated during a prior award that its expression level decreases in several models of mitochondrial disease and that if we force its expression back up, this has a surprisingly gratifying impact on reversing all of the disease parameters we were able to measure. Specifically, (a) its level in the cell is reduced in two separate mitochondrial disease models and also in other conditions where mitochondrial function is impaired such as inflammation and Niemann-Pick C1 disease, and (b) we can improve or almost totally ameliorate the pathological features of the diseases in cell models by artificially increasing the amount of MNRR1 by genetic manipulation. Most encouragingly, we went on to show, as a proof of principle, that we could identify a drug that stimulates MNRR1 expression and thereby relieve the pathology. Accordingly, our rationale for the current proposal is to build on previous results toward human interventions by now proposing to understand why MNRR1 levels decrease in all of these diverse conditions, to both discover and develop more potent drugs to enhance its expression, and to test MNRR1 enhancement in mouse models of several diverse mitochondrial diseases. Our overarching goal is to develop a deeper understanding of the pathways in which MNRR1 improves function so as to allow more targeted therapeutic interventions for individuals with mitochondrial disease. We can even speculate more broadly that we will eventually be able to aid individuals who are healthy but not optimally so due to reduced mitochondrial function. As described above, the proposed research expands on our work under a previous award. This proposal is thus an expansion project that addresses both the FY20 PRMRP Topic Areas and Area of Encouragement Mitochondrial Disease. We expect the impact will be high. Although we are targeting a pathway that impacts at least some traditional mitochondrial diseases, the more general importance is seen from the recent findings that mutations in MNRR1 are associated with neurological and neuromuscular diseases such as Parkinson’s disease. Thus, it may well help a diverse group of patients who have in common that mitochondrial dysfunction is part of their pathology.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110402
Entities
People
- Lawrence I. Grossman
Organizations
- United States Army
- Wayne State University