Neurodegenerative disorders, metabolic icebergs, and mitohormesis

Abstract

Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Hormesis; Huntington’s disease; Lumping; Mitochondria; Mitohormesis; Mitotypes; Parkinson’s disease; Splitting.

Fig. 1

Splitting perspective of neurodegenerative disorders. AD Alzheimer’s disease, VD vascular dementia, DLB dementia with Lewy bodies, FTD frontotemporal dementia, PD Parkinson’s disease, MSA multiple systems atrophy, PSP progressive supranuclear palsy, CBD corticobasal degeneration, ALS amyotrophic lateral sclerosis, PLS primary lateral sclerosis, PMA progressive muscular atrophy, HD Huntington’s disease, TDP-43 transactive response DNA binding protein 43, HTT Huntingtin

Fig. 2

Lumping perspective of neurodegenerative disorders. AD Alzheimer’s disease, PD Parkinson’s disease, ALS amyotrophic lateral sclerosis, HD Huntington’s disease

Fig. 3

The metabolic iceberg view of neurodegenerative disorders. This framework conveys the pathogenesis of each neurodegenerative disorder, which commences at the base, proceeds through the bulk, and eventually surfaces at the tip

Fig. 4

AD as a metabolic iceberg. AD Alzheimer’s disease, ATP adenosine triphosphate, TCA tricarboxylic acid, ETC electron transport chain, mtDNA mitochondrial DNA, APOE4 apolipoprotein E4

Fig. 5

PD as a metabolic iceberg. PD Parkinson’s disease, ATP adenosine triphosphate, ETC electron transport chain, mtDNA mitochondrial DNA, PRKN Parkin, PINK1 phosphate and tensin homolog-induced kinase 1

Fig. 6

ALS as a metabolic iceberg. ALS amyotrophic lateral sclerosis, TDP-43 transactive response DNA binding protein 43, ATP adenosine triphosphate, TCA tricarboxylic acid, ETC electron transport chain, mtDNA mitochondrial DNA, C9orf72 chromosome 9 open reading frame 72, SOD1 superoxide dismutase 1, FUS fused in sarcoma

Fig. 7

HD as a metabolic iceberg. HD Huntington’s disease, HTT Huntingtin, ATP adenosine triphosphate, ETC electron transport chain, mtDNA mitochondrial DNA