Mitochondrial Dysfunction in Age-Related Metabolic Disorders

Abstract

Aging is a natural biological process in living organisms characterized by receding bioenergetics. Mitochondria are crucial for cellular bioenergetics and thus an important contributor to age-related energetics deterioration. In addition, mitochondria play a major role in calcium signaling, redox homeostasis, and thermogenesis making this organelle a major cellular component that dictates the fate of a cell. To maintain its quantity and quality, mitochondria undergo multiple processes such as fission, fusion, and mitophagy to eliminate or replace damaged mitochondria. While this bioenergetics machinery is properly protected, the functional decline associated with age and age-related metabolic diseases is mostly a result of failure in such protective mechanisms. In addition, metabolic by-products like reactive oxygen species also aid in this destructive pathway. Mitochondrial dysfunction has always been thought to be associated with diseases. Moreover, studies in recent years have pointed out that aging contributes to the decay of mitochondrial health by promoting imbalances in key mitochondrial-regulated pathways. Hence, it is crucial to understand the nexus of mitochondrial dysfunction in age-related diseases. This review focuses on various aspects of basic mitochondrial biology and its status in aging and age-related metabolic diseases.

Keywords: aging; diabetes; metabolic diseases; mitochondrial calcium uniporter; mitochondrial dysfunction; mitophagy; obesity.

Fig 1:

Comparison of quantity and quality of mitochondria between healthy cell and ageing cell. Ageing process affects both quality and quantity of mitochondria thereby affecting multiple pathways leading to pathophysiological conditions mainly, metabolic disorders. The mitochondria in healthy cell has good membrane potential while the ageing cells have mitochondria with weak membrane potential affecting the efficiency of their function.

Fig 2:

Illustration on the impact of extrinsic factors implicating downstream effect due to failure of fission and fusion process. The dysfunction of proteins involved in fusion and fission along with loss of mitophagy leads to increase in ROS production and affects calcium uptake thereby affecting membrane potential and ATP production leading to cell senescence and pathological conditions including metabolic disorders. While the fusion process restores damaged mitochondria, the fission process helps in fragmentation of irreparable mitochondria. Abbreviations: mtDNA – mitochondrial DNA, ROS – Reactive Oxidation Species, Ca²⁺ - Calcium, ATP – Adenosine Triphosphate, OPA1 – Optic atrophy 1, Drp1- dynamin-related protein 1, MFN – Mitofusin, mPTP – mitochondrial permeability transition pore, PINK1 - PTEN-induced putative kinase 1.

Fig 3:

Depiction of various dysfunctional mitochondrial components that are dysfunctional and its related dysfunction/disorder (that are indicated by arrows) on outer and inner mitochondrial membrane. These components have been identified to be dysfunctional during ageing; however, therapies targeting these components are complicated due to the complexity of metabolic pathways possibly causing negative impact on other cellular function. Abbreviations: VDAC - Voltage-dependent anion-selective channel, Ca²⁺ - Calcium, Na⁺- Ca²⁺ exchanger, LETM 1– Leucine zipper/EF-hand-containing transmembrane protein 1, MCU – Mitochondrial calcium uniporter, MICU 1 – Mitochondrial calcium uptake 1, MICU 2 – Mitochondrial calcium uptake 2, MCUR1 – Mitochondrial calcium uptake regulator 1. EMRE – Essential MCU regulator, SIRT – Sirtuins, PGC1α - Peroxisome proliferator-activated receptor gamma coactivator 1α, OPA1 - Optic atrophy 1, iPLA2γ - Calcium-independent phospholipase A2γ, UCP – Uncoupling proteins, MFN – Mitofusin.