Mitochondrial pathways in human health and aging

doi:10.1016/j.mito.2020.07.007

Mitochondrion

Volume 54, September 2020, Pages 72-84

https://doi.org/10.1016/j.mito.2020.07.007 Get rights and content

Highlights

•
Mitochondrial dysfunction plays a role in many human diseases and is a hallmark of aging.
•
The precise mechanistic role of mitochondria in individual pathologies is often unclear.
•
Mitochondria influence a diversity of cellular systems beyond energetics and ROS.
•
Model organisms provide insight into the role of mitochondria in disease and longevity.
•
Genetic diseases and GWAS provide insight into the role of mitochondria in human health.

Abstract

Mitochondria are eukaryotic organelles known best for their roles in energy production and metabolism. While often thought of as simply the ‘powerhouse of the cell,’ these organelles participate in a variety of critical cellular processes including reactive oxygen species (ROS) production, regulation of programmed cell death, modulation of inter- and intracellular nutrient signaling pathways, and maintenance of cellular proteostasis. Disrupted mitochondrial function is a hallmark of eukaryotic aging, and mitochondrial dysfunction has been reported to play a role in many aging-related diseases. While mitochondria are major players in human diseases, significant questions remain regarding their precise mechanistic role. In this review, we detail mechanisms by which mitochondrial dysfunction participate in disease and aging based on findings from model organisms and human genetics studies.

Introduction

The importance of mitochondria in human health is underscored by the fact that neurodegeneration, cardiomyopathies, and musculoskeletal disorders can all result from mutations in mitochondrial or mitonuclear genes or environmental toxins that target mitochondria. Severe genetic defects causing mitochondrial dysfunction lead to mitochondrial diseases; these include Leigh Syndrome (LS), Mitochondrial Encephalopmyopathy with Lactic Acidosis and Stroke-like episodes (MELAS), Leber’s Hereditary Optic Neuropathy (LHON), and many others (Gorman, 2016, Alston et al., 2017). Among human age-related diseases, Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), metabolic disease, certain cancers, and age-related cardiovascular diseases (CVD) have all been directly associated with genetic variation in genes encoding mitochondrial proteins (Johnson, 2017, Kraja, 2019).

In addition to driving severe monogenic pathologies, mitochondrial dysfunction has been implicated in many chronic diseases in humans, particularly those associated with aging. Pathologies associated with aging are driven by dysregulation and dysfunction of tissue, cell, and molecular homeostatic pathways (Lopez-Otin et al., 2013). Across species, aging is associated with a decreased capacity to combat stress, an increased risk of multiple diseases, and increased frailty. Interventions targeting the underlying processes of aging are expected to have a significant impact on human health, as aging is the primary risk factor for many chronic diseases (Kaeberlein, 2013, Kennedy, 2014). Studies in model organisms have defined a number of mechanisms by which aging and age-related disease are modulated by mitochondrial function (Lopez-Otin et al., 2013). Mitochondria associated pathways of age-related disease include modulation of signaling through the mechanistic Target of Rapamycin (mTOR), insulin/insulin-like growth factor (IGF), AMP-activated protein kinase (AMPK), and sirtuin pathways; mitochondrial proteostatic mechanisms such as the mitochondrial unfolded protein response (mtUPR); mitochondrial retrograde signaling; energetics and ROS production; and redox balance, which influences nutrient signaling and stress responses (Dai et al., 2014, Hwang et al., 2012, Dai et al., 2012).

In this review, we will discuss mitochondrial structure, genetics, and functions in the context of human disease.

Section snippets

Mitochondrial structure and organization

Mitochondria are complex double-membrane organelles with functionally and compositionally distinct outer and inner membranes (Fig. 1) (Kuhlbrandt, 2015). The mitochondrial outer membrane (MOM) is similar in composition to the eukaryotic plasma membrane, separating the organelle from the cytoplasm and sequestering mitochondrial proapoptotic proteins, such as cytochrome c (Cyt C), a heme protein that carries electrons between complexes III and IV of the electron transport chain (see Mitochondrial

Mitochondrial genome

The prevailing view of the evolution of mitochondria is that mitochondria arose early in eukaryotic evolution as a result of endosymbiosis of a primordial eukaryote with free-living eubacteria (Sagan, 1967, Lazcano and Pereto, 2017). Over the course of eukaryotic evolution, the majority of genes in the primitive mitochondrial genome translocated to the nuclear genome (Bock, 2017). In fact, over 99% of genes encoding mitochondrial proteins are located in the nuclear genome (Johnson, 2017).

The electron transport chain

Respiratory metabolism, the aerobic catabolism of nutrients such as carbohydrates, fats, and proteins for energy production, takes place in the mitochondria. Complete catabolism of glucose, an important molecule for energy storage and transport, occurs in stages which are spatially separated between the cytoplasm and mitochondria. Glycolysis, which converts glucose into pyruvate, occurs in the cytoplasm, while the TCA cycle and oxidative phosphorylation (via the ETC) occur in the mitochondria.

Mitochondrial dynamics and quality control

Within individual cells, mitochondria form a highly dynamic network, constantly undergoing fission, fusion, biogenesis, and degradation through the process of mitophagy, the removal of mitochondria via autophagy (reviewed extensively in (Shi et al., 2018) (Rodger et al., 2018) (Tilokani et al., 2018) (Fig. 4). Fission and fusion are coordinated processes which regulate the morphology, size, and number of mitochondria in a cell (Whitley et al., 2019; Safiulina and Kaasik, 2013, Zorova, 2018).

Variants of strong effects

Rare genetic variants with strong effect can provide insight into biological processes that influence age-related pathologies. In particular, progeroid syndrome and inherited forms of classical age-related pathologies have revealed ‘longevity assurance’ pathways. Disruption of these pathways results in pathologic changes reminiscent of normal aging. While various forms of mitochondrial dysfunction have been associated with pathologies of aging, mutations in the mitochondrial genome or in

Discussion

It has become clear in recent years that mitochondria play a much more complex and nuanced role in human disease than simply acting as the cellular powerhouse, or as producers of toxin reactive oxygen species. Mitochondria modulate energy sensing and nutrient signaling, redox status, cellular proteostasis, intrinsic apoptosis, and a diversity of metabolic processes (Fig. 7). Given this wide array of biological functions, it is perhaps unsurprising that mitochondria have been genetically and

Funding

SCJ was supported by NIH R00 award GM126147. RB was supported by NIH T32GM095421.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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¹: These authors contributed equally to this work.

View full text

ReviewMitochondrial pathways in human health and aging

Highlights

Abstract

Introduction

Section snippets

Mitochondrial structure and organization

Mitochondrial genome

The electron transport chain

Mitochondrial dynamics and quality control

Variants of strong effects

Discussion

Funding

Declaration of Competing Interest

ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells

Biochim. Biophys. Acta

The genetics and pathology of mitochondrial disease

J. Pathol.

High oxidative damage levels in the longest-living rodent, the naked mole-rat

Aging Cell

Mitochondria retrograde signaling and the UPR mt: where are we in mammals?

Int. J. Mol. Sci.

Mitochondrial Heterogeneity

Front. Genet.

A Heterozygous NDUFV1 Variant Aggravates Mitochondrial Complex I Deficiency in a Family with a Homoplasmic ND1 Variant

J. Pediat.r

Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans

Nat. Commun.

The mitochondrial unfolded protein response and increased longevity: cause, consequence, or correlation?

Exp. Gerontol.

Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond

Free Radic. Biol. Med.

Witnessing genome evolution: experimental reconstruction of endosymbiotic and horizontal gene transfer

Annu. Rev. Genet.

Resolving complexity in mitochondrial disease: towards precision medicine

Mol. Genet. Metab.

Bioinformatics tools and databases to assess the pathogenicity of mitochondrial DNA variants in the field of next generation sequencing

Front. Genet.

Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers

Am. J. Hum. Genet.

Mitochondrial uncoupling proteins and energy metabolism

Front. Physiol.

Mitochondrial signaling: the retrograde response

Mol. Cell

Life-span extension by axenic dietary restriction is independent of the mitochondrial unfolded protein response and mitohormesis in Caenorhabditis elegans

J. Gerontol. A Biol. Sci. Med. Sci.

Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity

Aging Cell

The mitochondrial proteome and human disease

Annu. Rev. Genomics Hum. Genet.

mitochondrial retrograde signaling in mammals is mediated by the transcriptional cofactor GPS2 via direct mitochondria-to-nucleus translocation

Mol. Cell

Mitochondrial DNA mutations in primary leukemia cells after chemotherapy: clinical significance and therapeutic implications

Leukemia

Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis

J. Hum. Genet.

Collaboration between mitochondria and the nucleus is key to long life in Caenorhabditis elegans

Free Radic. Biol. Med.

Association of Uncoupling Protein 1 (UCP1) gene polymorphism with obesity: a case-control study

BMC Med. Genet.

The systems biology of mitochondrial fission and fusion and implications for disease and aging

Biogerontology

SirT3 and p53 deacetylation in aging and cancer

J. Cell Physiol.

Small molecule mitochondrial uncouplers and their therapeutic potential

J. Med. Chem.

Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance

J. Clin. Invest.

Variation in mitochondrial genotype has substantial lifespan effects which may be modulated by nuclear background

Aging Cell

Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean

Nature

Global changes in DNA methylation and hydroxymethylation in Alzheimer's disease human brain

Neurobiol. Aging

Mitochondrial retrograde signaling: triggers, pathways, and outcomes

Oxid. Med. Cell Longev.

Cardiac aging: from molecular mechanisms to significance in human health and disease

Antioxid Redox Signal

Mitochondrial oxidative stress in aging and healthspan

Longev Healthspan

Effects of the mitochondrial respiratory chain on longevity in C. elegans

Review
Mitochondrial pathways in human health and aging