Therapeutic Potential of Mitophagy-Inducing Microflora Metabolite, Urolithin A for Alzheimer's Disease

Abstract

Mitochondrial dysfunction including deficits of mitophagy is seen in aging and neurodegenerative disorders including Alzheimer's disease (AD). Apart from traditionally targeting amyloid beta (Aβ), the main culprit in AD brains, other approaches include investigating impaired mitochondrial pathways for potential therapeutic benefits against AD. Thus, a future therapy for AD may focus on novel candidates that enhance optimal mitochondrial integrity and turnover. Bioactive food components, known as nutraceuticals, may serve as such agents to combat AD. Urolithin A is an intestinal microbe-derived metabolite of a class of polyphenols, ellagitannins (ETs). Urolithin A is known to exert many health benefits. Its antioxidant, anti-inflammatory, anti-atherogenic, anti-Aβ, and pro-mitophagy properties are increasingly recognized. However, the underlying mechanisms of urolithin A in inducing mitophagy is poorly understood. This review discusses the mitophagy deficits in AD and examines potential molecular mechanisms of its activation. Moreover, the current knowledge of urolithin A is discussed, focusing on its neuroprotective properties and its potential to induce mitophagy. Specifically, this review proposes potential mechanisms by which urolithin A may activate and promote mitophagy.

Keywords: Alzheimer’s disease; mitophagy; neuroprotection; nutraceuticals; pomegranate; urolithin A.

Figure 1

Factors regulating mitohormesis and mitophagy. Adenosine monophosphate (AMP)-dependent kinase (AMPK) signalling, mitochondrial unfolded protein response (UPRmit), Silent information regulator of transcription (Sirtuin) signalling, inhibition of mammalian target of rapamycin (mTOR), caloric restriction and physical exercise induce low levels of ROS in mitochondria. ROS, at low levels, activate stress resistance mechanisms (mitohormesis), resulting in longevity. However, increased amounts of ROS in mitochondria are responsible for ageing, which is a major risk factor for AD and is influenced by APOE status and a variety of lifestyle factors. AMPK signalling, UPRmit, Sirtuin signalling, mTOR inhibition, caloric restriction and physical exercise also induce the mitophagy process, which is defective in AD.

Figure 2

Bacterial transformation of ellagitannins into urolithin A and B in humans. The ETs in ingested food are converted to EA in the human duodenum. In the lower intestinal tract, EA is converted to urolithin M-5, which can be converted into the intermediates urolithin E, urolithin M-6 and urolithin D. Urolithin E converts to urolithin M-7, while urolithin M-6 and urolithin D give rise to urolithin C. Urolithin C converts to isourolithin A and urolithin B respectively. Alternatively, urolithin M-7 and urolithin C are converted to urolithin A.

Figure 3

Hypothetical mechanisms of urolithin A in inducing mitophagy. Urolithin A activates SIRT1, SIRT3 [216] and AMPK. Activated AMPK increases PGC-1α levels [108] that directly increases mitochondrial biogenesis, which is in equilibrium with the mitophagy process. Activated AMPK also increases the activation of ULK1 [66]. Inhibition of mTOR1 is triggered by both urolithin A [217] and AMPK, which then activates ULK1 towards inducing mitophagy. The mTOR1 inhibition by Urolithin A may also induce the transcriptional activation of mitophagy via TFEBs. Urolithin A transcriptionally activates mitophagy via SIRT3-dependent FOXO activation [218,219].