Prohibitins in neurodegeneration and mitochondrial homeostasis

Abstract

The incidence of age-related neurodegenerative disorders has risen with the increase of life expectancy. Unfortunately, the diagnosis of such disorders is in most cases only possible when the neurodegeneration status is already advanced, and symptoms are evident. Although age-related neurodegeneration is a common phenomenon in living animals, the cellular and molecular mechanisms behind remain poorly understood. Pathways leading to neurodegeneration usually diverge from a common starting point, mitochondrial stress, which can serve as a potential target for early diagnosis and treatments. Interestingly, the evolutionarily conserved mitochondrial prohibitin (PHB) complex is a key regulator of ageing and metabolism that has been associated with neurodegenerative diseases. However, its role in neurodegeneration is still not well characterized. The PHB complex shows protective or toxic effects in different genetic and physiological contexts, while mitochondrial and cellular stress promote both up and downregulation of PHB expression. With this review we aim to shed light into the complex world of PHB's function in neurodegeneration by putting together the latest advances in neurodegeneration and mitochondrial homeostasis associated with PHB. A better understanding of the role of PHB in neurodegeneration will add knowledge to neuron deterioration during ageing and help to identify early molecular markers of mitochondrial stress. This review will deepen our understanding of age-related neurodegeneration and provide questions to be addressed, relevant to human health and to improve the life quality of the elderly.

Keywords: aging; mitochondria; nervous system; neurodegeneration; prohibitin (PHB).

FIGURE 1

The controversial role of PHB in neurodegeneration. (A) Mitochondrial damage may cause neurodegeneration and a differential expression of PHB as a consequence of the neurodegenerative process or the activation of mitophagy pathways. Inversely, the mitochondrial damage itself may cause an alteration of PHB expression levels which may trigger the neurodegenerative process. (B) The alteration of PHB levels in normal conditions due to mutations in other proteins may have beneficial and detrimental effects that will cause the protection against mitochondrial damage or the promotion of it, respectively. Green round arrows: protection against mitochondrial damage, which prevents neurodegeneration.

FIGURE 2

The prohibitin wheel. The role of PHBs in mitochondrial homeostasis is diverse. They directly participate in specific functions such as complex I assembly, protein aggregation and turnover, mitochondrial stress and mitophagy. They have been also described to have a role in ageing and neurodegeneration, although the exact mechanism by which they regulate lifespan or neuroprotection is still unclear. Nevertheless, a correct functioning of mitochondria is necessary, so a dysregulation of basic mitochondrial functions may lead to neurodegeneration.