AMPK is an energy sensor that controls turnover of cellular materials and metabolism in eukaryotic cells [^1,2]. Its holoenzyme is composed of one catalytic subunit, PRKAA/AMPKα, and two regulatory subunits, PRKAB/AMPKβ and PRKAG/AMPKγ [²]. Dysregulation of AMPK is involved in a number of cellular pathophysiological processes, such as diabetes, cancer, obesity, cardiovascular disease, etc [^3–5]. In general, AMPK can be activated in two cases: an increased AMP:ATP ratio [⁶], and glucose deprivation [⁷]. In the early stage of autophagy, AMPK either activates ULK1 [⁸] and BECN1 via direct phosphorylation [^9–11], or represses MTOR signaling via phosphorylating Raptor [¹²]. Under energy-deprivation conditions, AMPK regulates mitochondrial fission and mitophagy by phosphorylating the mitochondrial fission receptor MFF [¹³].

Mitochondria form a dynamic network in which fission, fusion, aggregation, and mitophagy occur. Mitochondria are in a constant balance of division and fusion, which is essential to maintain the quality and quantity of mitochondria [^14,15]. Outer mitochondrial membrane fusion is mediated by MFN1/2 [^16,17], and inner mitochondrial membrane fusion is mediated by OPA1 [^18,19]. The proteins that mediate mitochondrial division are MFF [^20,21], DNM1 L/DRP1 [²²], MIEF1/Mid51-MIEF2/MiD49 [²³], and possibly FIS1 [²⁴]. MFN1 and MFN2 form homodimers or heterodimers on two closely adjacent mitochondria to complete the fusion of the outer mitochondrial membrane [¹⁷]. In MFN2 knockout cells, however, mitochondria swell and fragment. In addition to being associated with each other, mitochondria also contact a variety of other organelles, one of which is the endoplasmic reticulum (ER) [²⁵]. The MAM is a specialized membrane region consisting of both mitochondria and ER, which are very close to each other. There is a certain spatial distance between the two organelles, and the distance and dynamic changes influence the physiological functions of the MAM, such as calcium ion exchange, lipid transfer and metabolism [^26,27].

Recent studies show that the MAM marks both the initiation site of autophagosome formation and the location of mitochondrial division [^28,29]. In addition to being an essential mitochondrial fusion protein, MFN2 is also a MAM protein and is responsible for tethering the ER and mitochondria [³⁰]. Some studies have shown that MFN2 is required for MAM formation, while others propose that it is a negative regulator of the MAM [^31,32]. Therefore, the functional role of MFN2 in formation and structural maintenance of the MAM is still controversial. Since the MAM is the point where autophagy occurs, it is possible that MFN2 may be involved in the regulation of autophagy. Previous studies have reported that MFN2 participates in autophagy in cardiomyocytes, and the authors observed the accumulation of autophagosomes in MFN2 KO cardiomyocytes, which appears to be caused by impaired fusion of autophagosomes with lysosomes in the absence of MFN2 [³³]. MFN2 is also engaged in the aging process of skeletal muscle by regulating mitochondrial autophagy [³⁴]. However, it is still unclear exactly how MFN2 is involved in the autophagy process and whether it is regulated by the upstream signals in the autophagy pathway. As mentioned above, AMPK is responsible for both autophagy induction and mitochondrial fission in energy-deprived cells, and the MAM is involved in both these processes, but it is largely unknown how AMPK regulates the MAM.