TECHNOLOGY

Mitochondria are rod-shaped organelles that can be considered the power generators of the cell, converting oxygen and nutrients into adenosine triphosphate (ATP). ATP is the chemical energy “currency” of the cell that powers the cell’s metabolic activities. This process is called aerobic respiration and is the reason animals breathe oxygen. Without mitochondria (singular, mitochondrion), higher animals would likely not exist because their cells would only be able to obtain energy from anaerobic respiration (in the absence of oxygen), a much less efficient process than aerobic respiration. In fact, mitochondria enable cells to produce 15 times more ATP than they could otherwise, and complex animals, like humans, need large amounts of energy to develop and survive.

Mitochondrial dynamics

Mitochondria generates ATP, the energy source for all cellular activities. Mitochondria are also involved in other essential cellular functions, including calcium sequestration, amino acid and lipid metabolism, balanced redox potential and programmed cell death. Mitochondria are very dynamic organelles that constantly undergo fission (division) and fusion. This process, called mitochondrial dynamics, is critical in maintaining healthy and functional mitochondria under both normal conditions and in response to stress. A defect in either fusion or fission limits mitochondrial motility, decreases energy production, increases oxidative stress and activates pro-apoptotic signaling thereby promoting cell dysfunction and death.
Disruptions in fission and fusion are implicated in many pathological conditions, including neurodegenerative diseases such as Huntington’s, Parkinson’s or Alzheimer’s Disease. Therefore, maintaining a proper balance between fission and fusion is a promising therapeutic approach to prevent cell damage and neurodegeneration. Specifically, fragmented mitochondria due to excessive fission are associated with these pathologies in cell culture and animal models and in patients. Mitoconix is developing a therapeutic peptide that is designed to selectively inhibit excess mitochondria fission and fragmentation for maintaining cellular integrity, thereby conferring neuroprotection and functional benefit.

Mitochondria and human disease

Mitochondria are essential for maintaining aspects of physiology as fundamental as cellular energy balance, the modulation of calcium signaling, in defining cellular redox balance, and they house significant biosynthetic pathways. Mitochondrial numbers and volume within cells are regulated and have an impact on their functional roles, while, especially in the CNS (central nervous system), mitochondrial trafficking is critical to ensure the cellular distribution and strategic localization of mitochondria, presumably driven by local energy demand. Maintenance of a healthy mitochondrial population involves a complex system of quality control, involving degrading misfolded proteins, while damaged mitochondria are renewed by fusion or removed by autophagy. It seems evident that mechanisms that impair any of these processes will impair mitochondrial function and cell signaling pathways, leading to disordered cell function which manifests as disease. As gatekeepers of cell life and cell death, mitochondria regulate both apoptotic and necrotic cell death, and so at its most extreme, disturbances involving these pathways may trigger untimely cell death. Conversely, the lack of appropriate cell death can lead to inappropriate tissue growth and development of tumors, which are also characterized by altered mitochondrial metabolism. The centrality of mitochondrial dysfunction to a surprisingly wide range of major human diseases is slowly becoming recognized, bringing with it the prospect of novel therapeutic approaches to treat a multitude of acute conditions and chronic diseases.

Neurodegenerative diseases

Neurodegenerative disease is an umbrella term for a range of conditions which primarily affect the neurons in the human brain.
Neurons are the building blocks of the nervous system which includes the brain and spinal cord. Neurons normally don’t reproduce or replace themselves, so when they become damaged or die they cannot be replaced by the body. Examples of neurodegenerative diseases include Parkinson’s, Alzheimer’s, and Huntington’s disease.
Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and / or death of nerve cells. This causes problems with movement or mental functioning. Dementias are responsible for the greatest burden of neurodegenerative diseases, with Alzheimer’s representing approximately 60-70% of dementia cases.

Huntington’s disease

Mitoconix’ initial focus is treating Huntington’s diseases (HD) given its Orphan Disease status (prevalence of ~5/100,000 worldwide) and ease of identifying affected individuals (genetic dominant disease). HD, which is caused by elongation of a polyglutamine repeat in the huntingtin protein, is manifest by progressive worsening in motor function, mental abilities and behavior. HD is usually diagnosed at the age of 30-50 years, with earlier onset correlating with longer polyglutamine repeat. HD patients suffer a slow and irreversible disease progression, usually lasting 10-20 years until inevitable death. Current treatment is symptomatic only. A disease-modifying therapy to slow HD progression remains an unmet clinical need. Mitpochondrial dynamics dysfunction leading to fragmentation and neuronal damage are associated with HD making it a promising therapeutic target in this disease.

Parkinson disease

Parkinson’s disease (PD) affects the nerve cells in the brain the produce dopamine. PD is a progressive disorder that affects movement. PD can also affect emotions and thinking cognition and patients have increased risk of developing dementia. Symptoms develop gradually, sometimes starting with a barely noticeable tremor in just one hand. But while a tremor may be the most well-known sign of Parkinson’s disease, the disorder also commonly causes stiffness or slowing of movement. Following diagnosis, treatments may relieve some disease symptoms, but no disease modifying therapy is currently available.

Most PD patients are classified as sporadic with no know history of the disease in their family. Approximately 15% of patients have family history of the diseases and several mutation in genes such as LRRK2 , PARKIN, or PINK1 were identified in these patients. Many of the genes liked to familial PD are associated with mitochondrial dysfunction, thus improving mitochondrial function is a promising disease modifying therapeutic strategy for the disease.