*3.3. Mitochondrial Dysfunction*

Mitochondria are the primary source of high-energy metabolism within the cell. Mitochondria are known as the powerhouse of the living cell. Mitochondria also regulate calcium homeostasis and play a role in scavenging free radicals and controlling programmed cell death and/or the apoptosis-signaling pathway [80]. Mitochondrial damage leads to reduced adenosine triphosphate (ATP) production, increased ROS generation, impaired calcium buffering, damage to mitochondrial DNA (mtDNA), an altered mitochondrial morphology, and alterations in mitochondrial fission and fusion. All these events eventually lead to cell death [81]. It is currently believed that the majority of ROS are generated by mitochondrial complexes I and III, likely due to the release of electrons by NADH and

dihydroflavine-adenine dinucleotide (FADH2) into the electron transport chain (ETC). Mitochondrial dysfunction is a characteristic of all chronic diseases and aging. It is characterized by a loss of efficiency in the ETC, as well as reductions in the synthesis of high-energy molecules [82]. These diseases include neurodegenerative diseases like Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, cardiovascular diseases, auto-immune diseases, diabetes, and others [83,84].

Mitochondria, as essential organelles, have a noteworthy role in the viability of neuronal cells. Excess ROS formation is due to complex I inhibition inducing impairments in the mitochondrial membrane potential (MMP) and the pro-apoptotic members are believed to permeabilize the outer mitochondrial membrane due to the formation of oligomeric pores, which permits the release of apoptogenic molecules from the intermembrane space. Recent studies have evaluated the neuroprotective activities of isolongifolene and structurally similar compounds, such as girinimbine, murrayazoline, and O-methylmurrayamine A isolated from *M. koenigii*. By using different in vitro assays, a study reported that the above bioactive compounds exhibited the ability to restore the MMP levels and repair the mitochondrial damage [85–87].
