Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer's disease

Abstract

Significance: Mitochondria and brain bioenergetics are increasingly thought to play an important role in Alzheimer's disease (AD).

Recent advances: Data that support this view are discussed from the perspective of the amyloid cascade hypothesis, which assumes beta-amyloid perturbs mitochondrial function, and from an opposite perspective that assumes mitochondrial dysfunction promotes brain amyloidosis. A detailed review of cytoplasmic hybrid (cybrid) studies, which argue mitochondrial DNA (mtDNA) contributes to sporadic AD, is provided. Recent AD endophenotype data that further suggest an mtDNA contribution are also summarized.

Critical issues and future directions: Biochemical, molecular, cybrid, biomarker, and clinical data pertinent to the mitochondria-bioenergetics-AD nexus are synthesized and the mitochondrial cascade hypothesis, which represents a mitochondria-centric attempt to conceptualize sporadic AD, is discussed.

FIG. 1.

The mitochondrion and its relationship to bioenergetic fluxes. Under normal conditions, neuron mitochondria may depend heavily on astrocyte-generated lactate as a carbon fuel source, and for this reason the reaction from lactate to pyruvate is explicitly indicated. The conversion of lactate to pyruvate definitely occurs in the cytosol, and some researchers believe this conversion may also occur within the mitochondrion itself. In general, though, carbon from several sources including carbohydrates, fatty acids, and amino acids can feed into the Krebs cycle. Reactions in the Krebs cycle reduce NAD⁺ to NADH and FAD to FADH₂. High-energy electrons from NADH enter the ETC at complex I, and high energy electrons from FADH₂ enter the ETC at complex II (not shown). As electrons flow through the ETC from high to low energy states, energy from those electrons is used to pump protons from the matrix to the intermembrane space and create a proton gradient. Due to electrochemical and pH gradients, protons in the intermembrane space are directed to re-access the matrix through complex V (the ATP synthase) and energy captured from this proton flux is used to phosphorylate ADP. Also shown is the mtDNA, which encodes catalytically critical parts of the complex I, III, IV, and V holoenzymes. CoQ, coenzyme; Cyt. C, cytochrome C.

FIG. 2.

Maternal inheritance, heteroplasmy, mitotic segregation, and threshold effects let mtDNA play a role in sporadic-appearing diseases. In females, diploid oogonia produce haploid oocytes during embryogenesis. If a heteroplasmic mtDNA mutation is present within an oogonium, oocytes with different mtDNA mutation burdens may result. In general, oocytes with high mutation levels are more likely to produce disease-affected offspring, but due to mitochondrial segregation that occurs after fertilization, different tissues may contain different levels of the mutation. Females with a high mutation burden in the nervous system but not their germ cells will themselves have a high risk of developing the neurologic disease and a low risk of transmission to the next generation. Females with a high mutation burden in their germ cells but not the nervous system have a high risk of transmission to the next generation and a low risk of developing the neurologic disease. Therefore, although the mtDNA mutation is maternally inherited, the disease it associates with appears mostly as a sporadic disorder with perhaps a subtle maternal inheritance bias.

FIG. 3.

The cybrid technique. mtDNA-depleted (ρ0) cells line and non-nucleated cytoplasts or platelets are mixed in the presence of a plasma membrane-disrupting detergent. After the detergent is diluted, membrane reconstitution generates some cells that contain a nucleus from a ρ0 cell, ρ0 cytosolic contents, and cytoplast cytosolic contents. Only cybrid cells that contain cytoplast mtDNA can go on to produce functional ETCs and survive a subsequent selection process. After the selection process is complete, the resulting cybrid cell line is used for biochemical and molecular analyses. Because cybrid cell lines created from a common ρ0 cell nuclear background have equivalent nuclear genes, and the cell expansion environment is equivalent between cell lines, biochemical or molecular differences between lines are expected to reflect differences between their mtDNA content.

FIG. 4.

The chain of events in AD cybrids. Altered COX function in AD cybrids presumably arises from and reflects mtDNA differences between the AD and control subjects that provided each cell line's mtDNA. Because mtDNA only encodes components of the respiratory chain, all other unique biochemical and molecular changes that occur in a cybrid line are consequences of its mtDNA-determined respiratory chain function.

FIG. 5.

Consequences of the mtDNA-encoded AD cybrid COX “defect”. Direct consequences of the mtDNA-encoded AD cybrid COX defect include increased ROS production and, perhaps to some extent, reduced ATP. The cell may try to compensate for its relatively tenuous bioenergetic status by increasing mtDNA synthesis. Several cybrid studies indicate ROS in turn activates a series of events, including increased Aβ production, activated stress signaling, and altered gene transcription. ROS, in conjunction with Aβ, also appears to depolarize mitochondria, activate apoptosis, and interfere with calcium homeostasis.

FIG. 6.

Bioenergetic failure occurs when mitochondrial function declines below a functional threshold. (A) If mitochochondrial durability and functional decline rates are equivalent, the time required to fall below the disease threshold is determined by the baseline level of mitochondrial function. (B) Given equivalent baseline levels of mitochondrial function, more durable mitochondria with slower rates of age-related decline will remain above the disease threshold longer than less durable mitochondria with accelerated rates of age-related decline.

FIG. 7.

The sporadic Alzheimer's disease mitochondrial cascade hypothesis. The mitochondrial cascade hypothesis postulates inheritance determines an individual's baseline mitochondrial function and durability. Both parents influence these parameters, but because mtDNA is maternally inherited, mothers have a bigger impact. The functional baseline determines the reserve bioenergetic capacity, while durability determines the rate at which an age-related decline in mitochondrial physiology occurs. When a functional threshold is reached, AD-associated histology changes such as Aβ deposition, tangle formation, and synaptic degradation follow. In the mitochondrial cascade hypothesis, Aβ oligomers, which have been shown to interfere with mitochondrial function in AD models, may contribute to the cascade but do not initiate it. This distinguishes the mitochondrial cascade hypothesis from the amyloid cascade hypothesis, which proposes Aβ oligomerization constitutes the most upstream event and initiates a neurodegenerative cascade.