Alterations in Mitochondrial Quality Control in Alzheimer's Disease

Abstract

Mitochondrial dysfunction is one of the earliest and most prominent features in the brains of Alzheimer's disease (AD) patients. Recent studies suggest that mitochondrial dysfunction plays a pivotal role in the pathogenesis of AD. Neurons are metabolically active cells, causing them to be particularly dependent on mitochondrial function for survival and maintenance. As highly dynamic organelles, mitochondria are characterized by a balance of fusion and fission, transport, and mitophagy, all of which are essential for maintaining mitochondrial integrity and function. Mitochondrial dynamics and mitophagy can therefore be identified as key pathways in mitochondrial quality control. Tremendous progress has been made in studying changes in these key aspects of mitochondrial biology in the vulnerable neurons of AD brains and mouse models, and the potential underlying mechanisms of such changes. This review highlights recent findings on alterations in the mitochondrial dynamics and mitophagy in AD and discusses how these abnormalities impact mitochondrial quality control and thus contribute to mitochondrial dysfunction in AD.

Keywords: Alzheimer’s disease; axonal transport; mitochondrial dynamics; mitochondrial quality control; mitochondrial transport; mitophagosome; mitophagy.

Figure 1

Mitochondrial fission and fusion. Mitochondria are dynamic organelles that undergo continuous fusion and fission events to intermix their lipids and contents. (A) Dynamin-related protein 1 (DRP1) regulates mitochondrial fission, which consists of two steps: first, DRP1 is recruited from the cytosol to the mitochondrial outer membrane (OM); second, its assemblage on the mitochondrial surface results in constriction of the mitochondria, leading to the separation of one mitochondrion into two entities. (B) Mitofusins 1 and 2 (MFN1/2) at the OM and optic atrophy 1 (OPA1) at the inner membrane (IM) orchestrate mitochondrial fusion, which involves MFN1/2-mediated OM fusion of two mitochondria, followed by OPA1-directed IM fusion. Mitochondrial fusion leads to elongated and highly interconnected mitochondria.

Figure 2

Microtubule-dependent motor-driven mitochondrial transport. Cytoplasmic dynein motors and kinesin-1 family (KIF5) of the KIF5 mediate mitochondrial transport. Dynein motors, the minus-end driven motors, carry out retrograde transport of mitochondria toward the soma of neurons. By contrast, KIF5 selectively moves mitochondria toward the plus-end of microtubules (MTs), and participates in anterograde transport from the soma to distal axons and synaptic terminals. Mitochondrial transport driven by KIF5 requires the mitochondrial rho (Miro)-Milton (or Miro-Trak) motor-adaptor complex. MIiro or MIRO is a mitochondrial outer membrane (OM) protein of the Rho GTPase family. In Drosophila melanogaster, Milton recruits KIF5 to mitochondria by binding to Miro. In a similar way, Trak1 and Trak2 (mammalian Milton orthologues) can bind to Miro1 and Miro2 (mammalian orthologues of Miro). The Miro1-Trak2 complex is an important regulator of mitochondrial transport in hippocampal neurons. KIF5 also associates with mitochondria and mediates mitochondrial anterograde transport via syntabulin, a KIF5 adaptor that binds to mitochondria via its carboxy-terminal transmembrane domain. Fasciculation and elongation protein zeta-1 (FEZ1), as well as RAN-binding protein 2 (RANBP2), are additional kinesin adaptors that may contribute to mitochondrial transport. Figure is modified from Sheng (2014).

Figure 3

Mitophagy. Mitophagy, which is initiated when damaged mitochondria are labeled for their subsequent recruitment into phagophore or isolation membranes, occurs through two mechanisms. First, upon loss of mitochondrial membrane potential, the E3 ubiquitin ligase Parkin is recruited from the cytosol to damaged mitochondria in a PTEN-induced putative kinase protein 1 (PINK1)-dependent manner. Parkin ubiquitinates mitochondrial proteins and causes mitochondria to become engulfed by phagophore or isolation membranes that then fuse with lysosomes. Second, outer mitochondrial membrane proteins, such as NIP3-like protein X (NIX; also known as BNIP3L), FUN14 domain containing 1 (FUNDC1), or cardiolipin externalized from the inner mitochondrial membrane phospholipid upon mitochondrial damage, bind to LC3 on the phagophore or isolation membranes, which mediate the sequestration of damaged mitochondria into mitophagosomes for lysosomal degradation.

Figure 4

Mitochondrial quality control. Mitochondrial quality control occurs at multiple levels in order to limit mitochondrial damage and ensure mitochondrial integrity. At the molecular level of defense, degradation of misfolded or damaged mitochondrial proteins is supported by the proteolytic system. Molecular chaperones and ATP-dependent proteases in the matrix and inner membrane (IM) of mitochondria degrade damaged proteins, stabilize misfolded proteins (thus preventing their aggregation), and/or dissolve protein aggregates, and thereby promote proteolysis. In addition, the cytosolic ubiquitin-proteasome system can participate in the quality control of mitochondrial proteins. At the organellar level, mitochondrial fusion and fission provide additional protection against mitochondrial damage. Damaged mitochondria can be repaired by fusion with healthy mitochondria, which allows the contents of healthy and dysfunctional mitochondria to be mixed. Fission, on the other hand, segregates mitochondria that have become irreversibly damaged or are fusion-incompetent and results in their subsequent elimination by autophagy. If the two quality control pathways described above are ineffective, dysfunctional mitochondria are eliminated by autophagy. One type of cargo-specific autophagy is mitophagy, which selectively removes damaged mitochondria. Figure is modified from Sheng and Cai (2012).

Figure 5

Functional interplay of mitochondrial transport and mitophagy in neurons. Upon mitochondrial membrane potential dissipation, Parkin-targeted mitochondria accumulate in the soma and proximal regions. Such compartmental restriction is attributed to altered motility of depolarized mitochondria, which exhibit reduced anterograde and relatively enhanced retrograde transport, thus reducing anterograde flux of damaged mitochondria into distal processes. This spatial process allows neurons to efficiently remove dysfunctional mitochondria from distal axons via the autophagy-lysosomal pathway in the soma, where mature lysosomes are mainly located. Damaged mitochondria at axonal terminals can also recruit Parkin for mitophagy once they are anchored by syntaphilin, or immobilized by turnover of the motor adaptor Miro on the mitochondrial surface. Autophagosomes containing engulfed mitochondria at axonal terminals are predominantly transported to the soma for maturation and for more efficient cargo degradation within acidic lysosomes. Figure is modified from Sheng (2014).

Figure 6

Abnormal mitochondrial quality control in Alzheimer’s disease (AD). Mitochondrial quality control is impaired at multiple levels in AD. At the molecular level, the mitochondrial presequence protease (PreP) degrades Aβ within mitochondria and thus reduces its toxic effects on mitochondria. However, the proteolytic activity of PreP is impaired as a result of increased reactive oxygen species (ROS) production in AD, thereby promoting accumulation of Aβ and Aβ-mediated mitochondrial toxicity. A decrease in proteasome activity could contribute to altered quality control of other presequence peptides and mitochondrial proteins. Mitochondrial quality control at the organellar level is also disrupted in AD. Elevated Drp1 levels or activity and reduced levels of Mfn1 and Mfn2 result in mitochondrial fragmentation and reduced fusion, thus preventing damaged mitochondria from being repaired through the fusion-mediated mixture of contents with healthy mitochondria. Enhanced mitophagy induction and defective lysosomal proteolysis result in aberrant accumulation of damaged mitochondria within mitophagosomes and autolysosomes, which also contribute to impaired mitochondrial quality control in AD. Moreover, defects in axonal transport and mitochondrial motility compromise mitochondrial quality control by hindering dysfunctional mitochondria from being returned to the soma for lysosomal degradation.