Experiential Trajectories of Weight Gain: A Qualitative Study of People With Larger Bodies' Understanding of Their Weight Changes Throughout Life in Norway.

Mitochondria are the central organelles that allow eukaryotic cells to efficiently convert nutrients into energy for cellular functions such as anabolic reactions, movement, and regulation. A reduction in the number of mitochondria or the occurrence of dysfunctional mitochondria leads to serious diseases such as the Leigh syndrome. However, such changes have also been connected to Alzheimer’s disease (AD) and many more diseases of different organ systems and occur during the aging process. Mitochondria are, therefore, the linchpin for the homeostasis of individual cells but also lay the foundation for a healthy, functional organism as a whole. Tissues and organs that consume a lot of energy show a loss of function early on if the mitochondria fail. This includes the brain, but also other organs such as the heart or the intestines, which have to provide high performance or are subject to permanent renewal. The importance of mitochondria for the integrity of neurons of the brain may become clear when looking at the almost altruistic behavior of microglia: a transfer of mitochondria into neurons was observed, for example, when neurons were exposed to α-synuclein or tau, hallmarks of Parkinson’s disease or AD (Scheiblich et al., 2024). By establishing tunneling nanotubes, healthy microglia donated the organelles to affected neurons and rescued them by reducing reactive oxidative species. Mitochondria comprise highly dynamic organelles that adjust their shape, location, and number by processes such as fusion and fission. Thus, local events such as noxae might imprint fast on them to serve actual cellular demands. In this perspective, we will focus on recent research regarding mitochondrial failure in AD and on how novel techniques that allow spatial resolution in analyzing these organelles contribute to widening the knowledge in this regard. AD is the most prevalent form of dementia in the elderly, accounting for approximately 70% of all dementia cases. It imposes a considerable burden of suffering not only on patients themselves but also on their caregivers, who are often close relatives. Despite decades of research, the pathogenesis of AD remains largely elusive (Scheltens et al., 2021). The majority of cases (up to 99%) are classified as sporadic, with no clearly defined genetic cause. However, increasing evidence suggests that mitochondrial dysfunction may be a hallmark of the disease. One of the earliest pathological changes observed in AD brains is impaired glucose metabolism. As neurons depend heavily on oxidative phosphorylation of glucose to generate adenosine triphosphate, this hypometabolism indicates a deficit in mitochondrial function. In contrast, astrocytes and oligodendrocytes predominantly meet their energy demands through aerobic glycolysis. Microglia primarily rely on oxidative phosphorylation under physiological conditions, but neuroinflammation can reprogram them toward a glycolysis-dominant metabolic phenotype (Cunnane et al., 2020). Previous studies have demonstrated reduced mitochondrial function in neurons and microglia in AD (Jörg et al., 2021; Li et al., 2022). This is evidenced by decreased expression of subunits of respiratory chain complexes, particularly complexes I, III, and IV, which is associated with diminished mitochondrial respiration (Askenazi et al., 2023). Additionally, altered mitochondrial morphology—characterized by fragmentation, disrupted cristae structure, impaired fusion, and increased fission—as well as defective mitophagy, have been observed in various models, including neuronal and microglial cultures, human induced pluripotent stem cell-derived neurons from AD patients, animal models, and post-mortem human brain tissue.