Xuemin Xu

Mitochondria are critical for cell health, and damaged or dysfunctional mitochondria have been strongly linked to various human diseases, particularly neurodegenerative disorders. Mitochondrial function is regulated by several mechanisms, including the regulation of mitochondrial shape, size, number, and morphology. Mitochondria constantly fuse together and separate apart, and this fusion and fission process is known as mitochondrial dynamics. These mitochondrial dynamics are modulated in response to various stimuli, and recent reports have demonstrated that mitochondria undergo hyperfusion under mild to moderate stress conditions, resulting in the formation of elongated filaments. This phenomenon is referred to as stress induced mitochondrial hyperfusion (SIMH). SIMH is associated with enhanced protection of mitochondria and improved cell viability under stress conditions. The induction of hyperfusion can be triggered by diverse stressors, each with distinct and unique mechanisms. This mini review will focus on these stressors and their corresponding mechanisms, as well as the subsequent effects on mitochondrial and cell health. Additionally, disease models which demonstrate a correlation between specific disease-related stress conditions and mitochondrial hyperfusion are discussed.

Presenilin-associated protein (PSAP) was originally identified as a mitochondrial proapoptotic protein. To further explore the apoptotic pathway that involves PSAP, our yeast two-hybrid screen revealed that PSAP interacts with a death receptor, DR6. DR6 is a relatively less common member of the death receptor family and has been shown to mediate the neurotoxicity of amyloid-β, mutant SOD1, and prion proteins and has also been implicated in the regulation of immune cell proliferation and differentiation. Our previous study showed that DR6 induces apoptosis via a unique mitochondria-dependent pathway different from the conventional death receptor-mediated extrinsic apoptotic pathways. Thus, the interaction of DR6 with PSAP established a direct molecular link between DR6 and mitochondrial apoptotic pathway. We investigated the possible role of PSAP in DR6-induced apoptosis. Interestingly, it was discovered that knockdown of PSAP strongly inhibited DR6-induced apoptosis. To further elucidate the mechanism by which PSAP mediates DR6-induced mitochondria-dependent apoptosis, our data demonstrated that knockdown of PSAP blocked DR6-induced Bax translocation and cytochrome c release from the mitochondria. Moreover, it was found that both PSAP and DR6 form complexes with Bax, but at different subcellular locations. The DR6-Bax complex was detected in the cytosolic fraction while the PSAP-Bax complex was detected in the mitochondrial fraction. The observation that knockdown of DR6 significantly reduced the amount of PSAP-Bax complex detected in mitochondria suggests a possibility that DR6-bound Bax is transferred to PSAP upon interaction with PSAP at the mitochondria, leading to cytochrome c release and eventually apoptosis.