Mitochondria dysfunction and impaired response to oxidative stress promotes proteostasis disruption in aged human cells

The plastic architecture of the mitochondrial network and its dynamic structure play crucial roles ensuring that varying energetic demands are rapidly met. Given the brain's high energy demand, mitochondria play a particularly critical role in neuronal and axonal energy homeostasis. With ageing physiological properties of the organism deteriorate, and are associated with loss of cellular homeostasis, accumulation of dysfunctional organelles and damaged macromolecules. Thus, mitochondrial loss of efficiency is likely to be both a cause and a consequence of ageing. Additionally distinct cellular events can contribute to oxidative stress, disruption of metabolism and mitochondria homeostasis, resulting in neuropathology. However, although the correlation between ageing and mitochondria disfunction is well established, the response to oxidative stress, particularly proteostasis, remains to be fully elucidated. The work here described explores the degradation of mitochondria oxidative stress-response mechanisms with ageing in human cells, addressing the physiological effects on proteostasis, focused on its role in differentiating between healthy and pathological ageing. Increased protein aggregation appears to be tightly related to impairment of ageing mitochondria response to oxidative stress, and antioxidative agents are shown to have a progressive protective effect with age; cells from old individuals show higher susceptibility to oxidative stress, in terms of protein aggregation, cell viability, or mitochondria homeostasis. These results support the antioxidant properties of flavonoids as a good therapeutic strategy for age-related diseases. Given their protective effect, this family of compounds can be of strategic therapeutic value for protein-aggregation related diseases.

This work was supported by the Integrated Programme of SR&TD ”pAGE”CENTRO-01-0145-FEDER-000003, PTDC/DTP-PIC/5587/2014, UID/BIM/04501/2013, EXPL/BTM-SAL/0902/2021, ERA-CVD/0001/2018-INNOVATION, EXPL/BIA-CEL/0358/2021, CI21-00276, a grant to DT from the Fundação para a Ciência e Tecnologia of the Ministério da Educação e Ciência (2020.02006.CEECIND), the Institute for Biomedicine—iBiMED (UIDB/04501/2020 and UIDP/04501/2020), University of Aveiro, and the Fundaçãopara a Ciência e Tecnologia of the Ministério da Educação e Ciência.

published