In a recent perspective published in Cell Death Discovery, a group of authors critically evaluated and interpreted the evidence linking mitochondrial dysfunction and metabolic changes to the pathogenesis of Alzheimer's disease (AD).
Study: Decoding metabolic signatures in Alzheimer’s disease: a mitochondrial perspective. Image Credit: nobeastsofierce/Shutterstock.com
Background
Cognitive deterioration and behavioral alterations are features of AD, a form of progressive neurodegenerative disorder. Amyloid β plaques, tau-containing neurofibrillary tangles, and neuronal degeneration are the physiological hallmarks of it. Though complex in its multi-factoriality, genetics, metabolism, and environmental exposures are central pathologies of AD.
Further research is essential to unravel the complex interplay between mitochondrial dysfunction and AD's pathogenesis. Elucidating the specific function of mitochondrial adaptations would guide us toward AD biomarkers as well as promising therapies directed at mitochondria-related pathways that might even change the nature of AD once we understand its true cause.
The role of mitochondria in cellular energy and metabolism
Mitochondria, the double-membrane organelles, are crucial for producing energy in the form of adenosine triphosphate (ATP). This is achieved by means of a chain of redox reactions in which the electrons from the various donors, such as glucose, are transferred to Oxygen.
Most eukaryotic cells have four respiratory complexes along with two electron carriers referred to as electron transport chain (ETC) that execute this process. The ETC is responsible for pumping protons across the mitochondrial inner membrane, thus building up a mitochondrial membrane potential that facilitates ATP synthesis through the oxidative phosphorylation (OXPHOS) pathway.
Mitochondria also make metabolic precursors, ion homeostasis, control cell death, and signal intracellularly; mitochondria are versatile and influential organelles of the cell.
Mitochondria in neurodegenerative diseases: A general overview
Aberrant mitochondrial activities have been implicated in a variety of human disorders, including metabolic syndromes and neurodegenerative diseases.
While the genetic links between mitochondria, inherited neuropathies, and metabolic disorders are well-established, the relationship between mitochondrial dysfunction and Alzheimer's disease (AD) is less clear, particularly when compared to other neurodegenerative diseases like Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).
However, recent clinical findings have started to shed light on this connection, particularly through the study of mutations in genes related to mitochondrial functions.
Mitochondria and AD: Investigating the link
Studies have reported that mutations in the PITRM1 gene, which encodes a mitochondrial matrix enzyme, may lead to the accumulation of amyloid-beta (Aβ) deposits, a hallmark of AD. Patients with pathogenic PITRM1 mutations exhibit symptoms and mitochondrial bioenergetics changes similar to those seen in AD. Although the role of mitochondria in Aβ degradation is still debated, evidence suggests that patients with PITRM1 mutations show reduced Aβ1–42 levels in cerebrospinal fluid, akin to those in AD patients. This points towards a potential involvement of mitochondrial dysfunction in the pathogenesis of AD.
Single nucleotide variants associated with late-onset AD can be found in Genome-wide association studies (GWAS) data and are in proximity to genes important in cellular bioenergetics. Although direct genetic evidence is still missing, alteration in brain glucose and oxygen metabolism has been observed along with mitochondrial respiratory defects and morphological abnormalities in tissues affected by AD.
Investigating mitochondrial dysfunction in AD: Clinical and experimental findings
Recent studies using positron emission tomography (PET) have revealed a progressive reduction in Complex I radioligand binding in early AD patients, suggesting a correlation between mitochondrial impairment and early cognitive decline.
Mitochondrial OXPHOS subunits and factors associated with mitochondrial proteostasis also exhibit dysregulated expression in postmortem tissue assessments, as well as in gene set enrichment analyses for AD subjects.
Interestingly, these changes are not limited to neurons but are also observed in glial cells, highlighting the widespread impact of mitochondrial dysfunction in AD.
Proteomic studies have detected significant changes in Complex I subunits and other components of the respiratory complexes in the brain tissues of AD patients. These findings are consistent with the idea that mitochondrial defects could serve as early biomarkers for AD. Further, proteomic analyses have revealed widespread alterations in the mitochondrial proteome in the cerebrospinal fluid, brain cortex, and serum of patients with mild cognitive impairment (MCI) and advanced AD. However, the changes are more pronounced in the advanced stages of the disease.
Conclusions
To summarize, the perspective surveys recent studies and postmortem assessments, investigating the link between changes in mitochondrial components and the development of AD.
The authors recognize significant advancements in the field while highlighting the limitations in detection methods and the availability of quality postmortem samples. They focus on human data, excluding literature on transgenic mice and other experimental models.
The review suggests that altered glucose and oxygen metabolism, possibly exacerbated by aging and various risk factors, might lead to mitochondrial bioenergetics impairment. This impairment could trigger a cycle of diminished neuronal resilience and increased vulnerability.
The authors emphasize the necessity for future research to conclusively determine mitochondria's role in AD pathogenesis and the potential therapeutic benefits of modulating mitochondrial bioenergetics in AD treatment strategies.
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