Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging?

Abstract

Down syndrome (DS), caused by trisomy of chromosome 21 (HSA21), is a complex condition associated with neurodevelopmental impairments and accelerated brain aging, often culminating in early-onset Alzheimer's disease (AD). Central to this accelerated aging is mitochondrial imbalance, characterized by disrupted energy metabolism, increased oxidative stress, impaired dynamics, and defective quality control mechanisms like mitophagy. These abnormalities exacerbate neuronal vulnerability, driving cognitive decline and neurodegeneration. This review examines the genetic and biochemical underpinnings of mitochondrial dysfunction in DS, with a focus on the role of HSA21-encoded genes. We also highlight how mitochondrial dysfunction, amplified by oxidative stress and HSA21 gene dosage effects, converges with cellular senescence and neuroinflammation to accelerate Alzheimer-like pathology and brain aging in DS. Finally, we discuss emerging therapeutic strategies targeting mitochondrial pathways, which hold promise for mitigating neurodegenerative phenotypes and improving outcomes in DS.

Figure 1.

HSA21 gene overexpression disrupts mitochondrial balance and accelerates brain aging in DS. T21 leads to the overexpression of multiple HSA21-encoded genes involved in mitochondrial function, including SOD1, APP, RCAN1, NRIP1, SUMO3, DYRK1A, and CBS. These genes collectively affect redox balance, mitochondrial dynamics, and biogenesis. Gene dosage imbalance disrupts mitochondrial homeostasis by increasing reactive oxygen species (ROS), impairing mitophagy, and promoting mitochondrial fragmentation. Mitochondrial bioenergetic dysfunction is marked by reduced mitochondrial membrane potential (MMP, ΔΨm), elevated mtDNA mutations, reduced mtDNA copy number, and decreased OXPHOS efficiency. These alterations result in ATP depletion and contribute to neurodevelopmental deficits, neurodegeneration, and hallmark features of DS, including early-onset Alzheimer's disease-like pathology. Together, they establish a trajectory of mitochondrial vulnerability that underlies and accelerates brain aging in individuals with DS.

Figure 2.

Early Onset of Cellular Senescence and Neuroinflammation in DS. Mitochondrial dysfunction and ROS drive the premature onset of cellular senescence as early as the prenatal stage, particularly in neural progenitor cells (NPCs). Hallmarks of senescence include heightened lysosomal SA-β-gal activity, genomic instability, elevated p21 expression, severe deficits in antioxidant defenses, mitochondrial impairment, nuclear lamina disruption, telomere shortening, and cell cycle arrest. The accumulation of senescent cells triggers a proinflammatory environment through the senescence-associated secretory phenotype (SASP), leading to chronic neuroinflammation and impaired neurogenesis. This persistent inflammatory state contributes to the progression of brain aging and neurodegeneration in DS.