Mitochondrial ATP production by oxidative phosphorylation (OXPHOS) is essential for cellular functions, such that mitochondria are known as the powerhouses of the cell (Verschueren et al., 2019). The mitochondrial ETC consists of five enzyme complexes in the inner membrane of the mitochondria. ETC generates a charge across the inner mitochondrial membrane, which drives ATP synthase (complex V) to synthesize ATP from ADP and inorganic phosphate.

Several studies have shown impairments of all five complexes in multiple areas of the AD brain (Kim et al., 2000, 2001; Liang et al., 2008). Mitochondrial dysfunction in AD is apparent from a decrease in neuronal ATP levels, which is associated with the overproduction of ROS, and indicates that mitochondria may fail to maintain cellular energy. A substantial amount of ATP is consumed in the brain due to the high energy requirements of neurons and glia. Since an energy reserve (such as fat or glucose) is not available in the central nervous system (CNS), brain cells must continuously generate ATP to sustain neuronal function (Khatri and Man, 2013). Mitochondria are the primary source of cellular energy production, but aged or damaged mitochondria produce excess free radicals, which can reduce the supply of ATP and contribute to energy loss and mitochondrial dysfunction in AD. Importantly, oxidative damage of the promoter of the gene encoding subunit of the mitochondrial ATP synthase results in reduced levels of the corresponding protein, leading to decreased ATP production, nuclear DNA damage to susceptible genes, and loss of function (Lu et al., 2004; Reed et al., 2008).

In advanced stages of AD, substantial nitration of ATP synthase subunits can take place, leading to the irregular function of the respiratory chain (Castegna et al., 2003; Sultana et al., 2006; Reed et al., 2009). Likewise, ATP-synthase lipoxidation occurs in the hippocampus and parietal cortex of patients with mild cognitive impairment (Reed et al., 2008). Compromised OXPHOS contributes to a characteristic mitochondrial dysfunction in AD brains, leading to decreased ATP production, elevated oxidative stress, and ultimately cell death (Reddy, 2006; Reddy and Beal, 2008; Du et al., 2012). The specific mechanisms of OXPHOS deficiency in AD remain a long-standing scientific question, but the role of mitochondrial F₁F_o ATP synthase dysfunction in AD-related mitochondrial OXPHOS failure is emphasized by emerging evidence (Beck et al., 2016; Gauba et al., 2019).