Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment

Abstract

Summary Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system (CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological‐based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain (ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases.

Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases

“…4). In Alzheimer disease, elevated ROS levels precede and promote the formation of β-amyloid- and tau-containing plaques and neurofibrillary tangles 103 , which further impair OXPHOS complexes 110 . A similar self-promoting loop occurs in familial Parkinson disease, in which disease-causing proteins increase ROS, impair OXPHOS and ultimately trigger neuronal death 103 .…”

“…Activation of PGC1α alleviates mitochondrial dysfunction and other ageing defects in fibroblasts from patients with HGPS 105 , although the beneficial effects of PCG1α activation in vivo appear to be tissue-specific and dependent on the duration and extent of activation 37 . Decreased PGC1α activity occurs in Alzheimer disease and Parkinson disease and is implicated in CKD-associated muscular dystrophy 110,119 . Diminished metabolic activation of the PGC1α upstream regulators SIRT1 and AMPK in HGPS, ageing and AADs likely underlies the observed decrease in PGC1α activity 26 .…”

Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease

“…Prolonged and frequent occurrence of high cytosolic Ca 2+ has been suggested to compromise mitochondrial function [85, 86, 93, 94]. This together with the observed Ca 2+ up-regulation and mitochondrial dysfunction in several neurodegenerative diseases could provide a link between Ca 2+ rise in these diseases and cytotoxicity [95–103]. The studies in Refs.…”

Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches

“…The segregation of impaired mitochondria due either to fission or to inhibition of fusion mechanism is hypothesized to be a requirement for this mitophagic degradation [16]. Mitophagy impairments are involved in the development of several neurodegenerative diseases [17].…”