Mitochondria are a cell’s powerhouse and also have a vital part in cellular processes. The emerging role of mitochondria in several crucial processes highlights their cellular and physiological importance. Mitochondrial homeostasis mechanisms, including proteostasis pathways, are vital for mitochondrial health. Failure of these processes has an important role in establishment of numerous complex disease conditions, such as neurodegeneration and imperfect ageing. However, details of mitochondrial impairments and their contribution to the pathology of neurodegeneration are poorly understood. This review systematically discusses the involvement of mitochondrial homeostasis mechanisms and their role in rejuvenating cellular health and fitness. We also focus on various cellular protein quality control mechanisms essential for mitochondrial proteostasis and how their failure leads to mitochondrial functional disturbances observed in disease conditions. We discuss recent findings based on mitostasis-associated chaperones, mitoproteases, and autophagy responses, which can lead to emergence of new possible therapeutic interventions against complex diseases. (Figure presented.).