Potential Role of Mic60/Mitofilin in Parkinson's Disease

Abstract

There are currently no treatments that hinder or halt the inexorable progression of Parkinson's disease (PD). While the etiology of PD remains elusive, evidence suggests that early dysfunction of mitochondrial respiration and homeostasis play a major role in PD pathogenesis. The mitochondrial structural protein Mic60, also known as mitofilin, is critical for maintaining mitochondrial architecture and function. Loss of Mic60 is associated with detrimental effects on mitochondrial homeostasis. Growing evidence now implicates Mic60 in the pathogenesis of PD. In this review, we discuss the data supporting a role of Mic60 and mitochondrial dysfunction in PD. We will also consider the potential of Mic60 as a therapeutic target for treating neurological disorders.

Keywords: Mic60/mitofilin; Parkinson’s disease; mitochondria; mitochondrial dynamics; neurodegeneration.

FIGURE 1

Mic60: Mitochondrial cristae structure maintenance and proposed phospho-regulation. (A) Mic60 is an inner mitochondrial membrane protein and key component of the MICOS and MIB protein complexes, which bridge inner membrane cristae junctions and inner-outer membrane contact sites, respectively. Maintenance of cristae structure by MICOS also regulates function of the mitochondrial Electron Transport Chain Complexes (I, II, III, and IV) and ATP synthase (F₀-F₁). (B) It is proposed that under normal conditions, Mic60 interacts with and is phosphorylated by PINK1 at a basal rate, thus regulating its ability to maintain normal cristae structure. (C) Under conditions in which PINK1 expression is decreased, PINK1 kinase function is inactivated, or Mic60 expression is reduced, the mitochondrial cristae structure is not maintained. This leads to mitochondria exhibiting characteristic onion ring-like whorls of the inner membrane or formation of large vacuoles within the mitochondrion. This is accompanied by decreased membrane potential (Δψ) and respiratory function. (D) Under conditions in which PINK1 phosphorylation of Mic60 is increased or Mic60 expression is increased, mitochondria can exhibit increased numbers of inner membrane cristae structures and cristae junctions. This is accompanied by highly coupled respiratory function. (E) One proposed mechanism of PINK1’s effects on Mic60 is that phosphorylation increases the ability of Mic60 to oligomerize with itself and, presumably, the MICOS complex, leading to increased inner membrane structural integrity. (F) In a cellular state in which cAMP levels and PKA activation are low, PINK1 can also interact with Mic60 and be stabilized on the surface of mitochondria, aiding in its function to recruit Parkin to damaged mitochondria. (G) However, in apparent opposition to the PINK1-Mic60 interaction, PKA activation and phosphorylation of Mic60 destabilizes the MICOS complex and decreases the ability of PINK1 to stabilize on the mitochondrial surface, preventing the recruitment of Parkin to damaged mitochondria.