Inhibiting Mitochondrial Permeability Transition Pore Opening to Treat Mitochondrial Myopathy
Abstract
Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Topic Area: Mitochondrial disease. Strategic Goal: Treatment: Develop and test novel treatment strategies for mitochondrial diseases, especially those ready to progress to the clinic, including repurposing existing drugs or non-prescription treatment option. Critical problem to be addressed: Mitochondria provide the bulk of energy for the cell and perform numerous other functions for the cell. However, mitochondria can become dysfunctional and cause disease. Primary mitochondrial disease is caused by mutations in nuclear- or mitochondrial-encoded DNA, or from drugs or toxins. Energy deficit, per se, is not the major driver of pathology in mitochondrial disease. Rather, mitochondrial dysfunction initiates adaptive and maladaptive changes in metabolism and cell signaling that are linked to pathology. However, what initiates, sustains, and modifies these changes in vivo, and how they lead to myopathy and worsening of myopathy, are unknown. This knowledge could reveal novel therapeutic strategies. Skeletal muscle is among the most severely affected organs; mitochondrial myopathy is characterized by a poor capacity for physical activity, muscle wasting and weakness. Furthermore, when a muscle biopsy can be obtained allowing for the muscle to be imaged at very high resolution, swollen mitochondria with little internal structure (cristae) are evident and suggest that a process called opening of the mitochondrial permeability transition pore (mPTP) is occurring in the muscle. Opening of the mPTP prevents mitochondria from producing energy and also might cause cell death. Evidence for opening of the mPTP is also evident in the muscle of mouse models of mitochondrial myopathy. The uptake of Ca2+ into mitochondria can be a potent trigger for mPTP opening, especially in conjunction other aspects of mitochondrial function that are frequently present when mitochondria are severely dysfunctional as occurs in mitochondrial disease. We have made the novel observation that the protein complex that allows mitochondrial Ca2+ uptake – called the uniporter – is greatly increased in abundance in mouse models of mitochondrial disease; this was detected from our own data from two different mouse models of mitochondrial myopathy, and in published data from six other mouse models of mitochondrial myopathy. We nominate the uniporter and the mPTP as drivers of mitochondrial myopathy, and thus as potential therapeutic targets. Indeed, small molecules that target the mPTP have been developed and continue to be in development, as are small molecules that target the uniporter. Basic experimental approach: Basic approach: Opening of the mPTP will be inhibited by (1) genetic knockdown of the Ca2+ uniporter or (2) pharmacological (NIM811) or direct genetic targeting of mPTP. These strategies will be performed on two different mouse models of mitochondrial myopathy (loss of mitochondrial phosphate carrier, loss of Frataxin). Outcomes: (1) Signs of mPTP opening will be evaluated by imaging muscle using electron microscopy. (2) Exercise capacity will be tested by treadmill running using defined protocols. (3) Whole-body O2 consumption during treadmill running will be measured to evaluate mitochondrial energy production during exercise. (4) Blood lactate will be measured at rest and after treadmill running, to estimate the reliance on non-mitochondrial energy production. (5) Extent of Integrated Stress Response (ISR) activation will be analyzed in muscle by measuring well-accepted outcomes of ISR activation. (6) ISR activation can lead to lower muscle mass; muscle mass will be measured and muscle cross-sectional area evaluated by histology. Innovation: There are three innovative aspects of this proposal. First, the idea to target the mPTP in the context of mitochondrial myopathy has, to our knowledge, never been proposed and thus is innovative. The second innovative aspec
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310798
Entities
People
- Erin L Seifert
Organizations
- Thomas Jefferson University
- United States Army