Leigh syndrome, also known as subacute necrotizing encephalomyelopathy, is a hereditary progressive neurodegenerative disease. In 1951, British neuropathologist Denis Leigh first described a 7-month-old infant with symptoms of loss of pupillary reflection, rigid limbs, and deafness. The patient died 3 days after the onset of the disease. Autopsy revealed symmetrical thalamus, midbrain, pons, medulla oblongata, and posterior cord injuries.
Mitochondrial complex I regenerates NAD+ and proton pumps to produce tricarboxylic acid (TCA) cycle function and ATP, respectively. Mitochondrial complex I dysfunction is associated with many brain diseases, including Leigh syndrome and Parkinson's disease.
On June 22, 2020, the team of Navdeep S. Chandel of Northwestern University published a research paper entitled "NAD+ Regeneration Rescues Lifespan, but Not Ataxia, in a Mouse Model of Brain Mitochondrial Complex I Dysfunction" in Cell Metabolism. The research generated A mouse that conditionally expresses yeast NADH dehydrogenase (NDI1), a single enzyme that can replace the NAD + regeneration ability of the 45 subunit mammalian mitochondrial complex I without a proton pump.
In a mouse model of Leigh syndrome driven by the deletion of NDUFS4 (a subunit of mitochondrial complex I), NDI1 expression is sufficient to significantly extend lifespan (lifespan from 45 days to more than 365 days) without significant improvement in motor function. Therefore, the activity of mitochondria I in the brain supports the survival of the body through its NAD + regeneration, and optimal movement control requires the bioenergy function of mitochondrial complex I.
The electron transport chain of mitochondria provides proton power, which drives oxidative phosphorylation and oxidizes NADH to NAD +, thereby allowing the tricarboxylic acid (TCA) cycle to proceed. The TCA cycle provides the basis for amino acids, nucleic acids, carbohydrates and lipids. In mammals, mitochondrial complex I (MC1) is a 45-subunit complex that couples the oxidation of NADH with a proton pump to generate ATP. The dysfunction of MC1 is related to neurodegenerative diseases such as Parkinson's disease and Leigh syndrome. Considering the important role of MC1 in NAD+ regeneration and ATP production, it is difficult to analyze which of these protein subunits controls the dysfunction of complex tissues such as the brain.
In general, the bioenergy and biosynthesis of MC1 are inseparable, because the oxidation of NADH and the reduction of ubiquinone are related to protons crossing the inner mitochondrial membrane to generate proton power. In order to analyze these two key functions of MC1 in vivo, the researchers used single-subunit yeast NADH dehydrogenase (NDI1). In yeast, NDI1 is the main entry point into the electron transport chain, catalyzing the oxidation of NADH in a substrate like MC1. However, NDI1 does not promote the production of ATP by proton pump. Previously, NDI1 has been expressed in mammalian cells in vitro and through viral delivery, and when expressed ectopic, NDI1 can extend the lifespan of fruit flies (male fruit flies can be extended by 30-40%; female fruit flies can be extended by 10-20 %;).
Leigh syndrome, also known as subacute necrotizing encephalomyelopathy, is a hereditary progressive neurodegenerative disease. In 1951, British neuropathologist Denis Leigh first described a 7-month-old infant with symptoms of loss of pupillary reflection, rigid limbs, and deafness. The patient died 3 days after the onset of the disease. Autopsy revealed symmetrical thalamus, midbrain, pons, medulla oblongata, and posterior cord injuries.
The researchers used the Cre/Lox method to cause the conditional deletion of NDUFS4 and the expression of yeast NDI1 in mice. NDUFS4 is an 18 kDa auxiliary subunit involved in the assembly and stability of MC1. NDUFS4-deficient mice recapitulate many characteristics of human Leigh syndrome, including the development of bilateral high-intensity MRI lesions, glial activation, seizures, ataxia, growth regression, and early death. It is worth noting that the deletion of NDUFS4 will not lead to the complete loss of MC1 function, and the reduction of the enzymatic activity of MC1 varies from tissue to tissue.
Interestingly, previous studies have shown that interventions that specifically target NADH elevation, such as NAD precursor supplementation, mTOR inhibition and inhibition of mitochondrial serine catabolism, and hypoxia therapy have proven to be beneficial in life and function. A recent study showed that conditional loss of NDUFS4 in GABAergic neurons (Gad2-Cre) or glutamatergic neurons (Vglut2-Cre) leads to seizures or ataxia and abnormal breathing, respectively.
The graduate student became a kind of mouse that conditionally expresses yeast NADH dehydrogenase (NDI1), which is a single type of NAD + regeneration ability that can replace the 45 subunits of mammalian mitochondrial complex I without a proton pump. Enzyme. In a mouse model of Leigh syndrome driven by the deletion of NDUFS4 (a subunit of mitochondrial complex I), NDI1 expression is sufficient to significantly extend life span (from 45 days to more than 365 days) without significantly improving motor function. Therefore, the activity of mitochondria I in the brain supports the survival of the body through its NAD + regeneration, and optimal movement control requires the bioenergy function of mitochondrial complex I.